Triaminopyrimidine compounds useful for preventing or treating malaria

ABSTRACT

The present invention relates to triaminopyrimidines and to pharmaceutically acceptable salts thereof, to their use in the treatment and/or prevention of malaria caused by  plasmodium  species, and to their methods of preparation.

FIELD OF THE INVENTION

The present invention relates to triaminopyrimidine compounds,pharmaceutical compositions thereof, and methods of use. In addition,the present invention relates to therapeutic methods for the treatmentof parasitic infections caused by Plasmodium species.

BACKGROUND OF THE INVENTION

Malaria is caused by protozoan parasites of the genus Plasmodium thatinfect and destroy red blood cells, leading to fever, severe anemia,cerebral malaria and, if untreated, death. Plasmodium falciparum is thedominant species in sub-Saharan Africa, and is responsible forapproximately 600,000 deaths each year. The disease burden is heaviestin African children under 5 years of age and in pregnant women.Plasmodium vivax causes 25-40% of the global malaria burden,particularly in South and Southeast Asia, and Central and South America.The other three main species that are known to infect humans arePlasmodium ovale, Plasmodium knowelsi and Plasmodium malariae.Plasmodium species, for example, P. falciparam and P. vivax which areknown to cause malaria are particularly important because of thedevelopment of resistant strains which are both difficult to treat anddifficult to eradicate from the hospital and community environment oncethey have established infection. Examples of such strains arechloroquine resistant, pyrimethamine resistant, artemisinin resistantstrains of Plasmodium falciparum.

Malaria is a disease that is prevalent in many developing countries.Approximately 40% of the world's population lives in countries where thedisease is endemic; approximately 247 million people suffer from thedisease every year.

Consequently, in order to overcome the threat of widespread multi-drugresistant parasites, there is an urgent need to develop new antimalarialagents particularly those with either a novel mechanism of action and/orcontaining new pharmacophoric groups. The present invention aims ataddressing such draw backs in the art associated with the management andtreatment of malaria.

SUMMARY OF THE INVENTION

In accordance with the present invention, the applicants have herebydiscovered compounds that possess the ability to act as anti-malarialagents.

The present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts thereof, wherein HAR, R¹, R², R³,R⁴, R⁵ and R⁶ are defined below.

The present invention also provides processes for the preparation ofcompounds of Formula (I), pharmaceutical compositions containing them asthe active ingredient, their use as medicaments, methods of using suchcompounds, and their use in the manufacture of medicaments for theprevention and treatment of malaria in warm blooded animals such ashuman being.

It is expected that typical compounds of Formula (I) possess beneficialefficacious, metabolic, toxicological, and/or pharmacodynamicproperties.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of Formula (I):

as well as complexes, hydrates, solvates, or polymorphs, tautomers,geometrical isomers, optically active forms and pharmaceuticallyacceptable salts thereof, wherein: HAR is a 5 membered heteroaryl ringsystem selected from the following group:

R¹ in each occurrence is independently selected from H, C₁₋₆ alkyl, CF₃and C₃-C₅ cycloalkyl;

R² in each occurrence is independently selected from halo, —CN and C₁₋₆alkyl;

R³ each occurrence is selected from H, C₁₋₆ alkyl, C₃-C₅ cycloalkyl andCF₃;

R⁴ in each occurrence is independently selected from H and C₁₋₆ alkyl;

R⁵ in each occurrence is independently selected from H and C₁₋₆ alkyl;and

R⁶ in each occurrence is independently selected from H and C₁₋₆ alkyl.

In some embodiments, R¹ is methyl.

According to another embodiment, R² is halogen.

In some embodiments, R² is selected from fluorine, chlorine and CN.

According to a further embodiment, R² is F or Cl.

According to another embodiment, R³ is C₃-C₅ cycloalkyl such ascyclobutyl or cyclopropyl.

According to another embodiment, R³ is cyclopropyl.

According to another embodiment, R³ is C₁₋₆ alkyl such as ethyl.

In some embodiments, R³ is selected from cyclobutyl, ethyl andcyclopropyl.

According to another embodiment, R⁴ is H.

According to another embodiment, R⁴ is C₁₋₆ alkyl such as methyl.

In some embodiments, R⁴ is selected from hydrogen and methyl.

In some embodiments, R⁵ is hydrogen.

According to another embodiment, R⁶ is H.

According to another embodiment, R⁶ is C₁₋₆ alkyl such as methyl.

In some embodiments, R⁶ is selected from hydrogen and methyl.

In some embodiments, HAR is selected from the following group:

According to another embodiment, HAR is selected from

According to another particular embodiment, is provided a compound ofFormula (I) wherein wherein R¹ is methyl; R² is selected from fluorine,chlorine and CN; R³ is selected from cyclobutyl, ethyl and cyclopropyl;R⁴ is selected from hydrogen and methyl; R⁵ is hydrogen; R⁶ is selectedfrom hydrogen and methyl; and HAR is selected from the following group:

In this specification the prefix C_(x-y) as used in terms such asC_(x-y) alkyl and the like (where x and y are integers) indicates thenumerical range of carbon atoms that are present in the group; forexample, C₁₋₆ alkyl includes C₁alkyl (methyl), C₂alkyl (ethyl), C₃ alkyl(propyl and isopropyl) and C₄ alkyl (butyl, 1-methylpropyl,2-methylpropyl, and t-butyl).

Unless specifically stated, the bonding atom of a group may be anysuitable atom of that group; for example, propyl includes prop-1-yl andprop-2-yl.

Alkyl—As used herein the term “alkyl” refers to both straight andbranched chain saturated hydrocarbon radicals having the specifiednumber of carbon atoms. References to individual alkyl groups such as“propyl” are specific for the straight chain version only and referencesto individual branched chain alkyl groups such as ‘isopropyl’ arespecific for the branched chain version only. In one aspect, “C₁₋₆alkyl”may be methyl.

Cycloalkyl—As used herein, the term “cycloalkyl” refers to a saturated,partially saturated, or unsaturated, mono or bicyclic carbon ring thatcontains 3 to 12 ring atoms, of which one or more —CH₂— groups may beoptionally replaced with a corresponding number of —C(O)— groups.Illustrative examples of “cycloalkyl” include, but are not limited to,adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, indanyl, naphthyl, oxocyclopentyl,1-oxoindanyl, phenyl, and tetralinyl.

3- to 6-Membered Cycloalkyl—In one aspect, “cycloalkyl” may be “3- to6-membered cycloalkyl.” As used herein, the term “3- to 6-memberedcycloalkyl” refers to a saturated, partially saturated, or unsaturatedmonocyclic carbon ring containing 3 to 6 ring atoms, of which one ormore —CH₂— groups may be optionally replaced with a corresponding numberof —C(O)— groups. Illustrative examples of “3- to 6-membered cycloalkyl”include cyclopropyl, cyclobutyl, cyclopentyl, oxocyclopentyl,cyclopentenyl, cyclohexyl, and phenyl.

Halo—As used herein, the term “halo” includes fluoro, chloro, bromo andiodo. In one aspect, the term “halo” may refer to fluoro, chloro, andbromo. In another aspect, the term “halo” may refer to fluoro andchloro. In another aspect, the term “halo” may refer to fluoro

Effective Amount—As used herein, the phrase “effective amount” means anamount of a compound or composition which is sufficient enough tosignificantly and positively modify the symptoms and/or conditions to betreated (e.g., provide a positive clinical response). The effectiveamount of an active ingredient for use in a pharmaceutical compositionwill vary with the particular condition being treated, the severity ofthe condition, the duration of the treatment, the nature of concurrenttherapy, the particular active ingredient(s) being employed, theparticular pharmaceutically-acceptable excipient(s)/carrier(s) utilized,the route of administration, and like factors within the knowledge andexpertise of the attending physician.

Pharmaceutically Acceptable—As used herein, the term “pharmaceuticallyacceptable” refers to those compounds, materials, compositions, and/ordosage forms which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of human beings and animalswithout excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio.

In the context of the present invention are encompassed pharmaceuticallyacceptable salts, complexes, hydrates, solvates, or polymorphs,tautomers, geometrical isomers, optically active forms andpharmaceutically active derivatives of compounds of the invention.Unless stated to the contrary, the present invention includes all suchpossible diastereomers as well as their racemic mixtures, theirsubstantially pure resolved enantiomers, all possible geometric isomers,and pharmaceutically acceptable salts thereof. Mixtures ofstereoisomers, as well as isolated specific stereoisomers, are alsoincluded. During the course of the synthetic procedures used to preparesuch compounds, or in using racemization or epimerization proceduresknown to those skilled in the art, the products of such procedures canbe a mixture of stereoisomers. The term “malaria” includes disease andconditions related to an infection by Plasmodium.

As used herein, “treatment” and “treating” and the like generally meanobtaining a desired pharmacological and physiological effect. The effectmay be prophylactic in terms of preventing or partially preventing adisease, symptom or condition thereof and/or may be therapeutic in termsof a partial or complete cure of a disease, condition, symptom oradverse effect attributed to the disease. The term “treatment” as usedherein covers any treatment of a disease in a mammal, particularly ahuman, and includes: (a) preventing the disease from occurring in asubject which may be predisposed to the disease but has not yet beendiagnosed as having it; (b) inhibiting the disease, i.e., arresting itsdevelopment; or relieving the disease, i.e., causing regression of thedisease and/or its symptoms or conditions.

The term “effective amount” includes “prophylaxis-effective amount” aswell as “treatment-effective amount”.

The term “prophylaxis-effective amount” refers to a concentration ofcompound of this invention that is effective in inhibiting, decreasingthe likelihood of the disease by malarial parasites, or preventingmalarial infection or preventing the delayed onset of the disease bymalarial parasites, when administered before infection, i.e. before,during and/or slightly after the exposure period to malarial parasites.

The term “prophylaxis” includes causal prophylaxis, i.e. antimalarialactivity comprising preventing the pre-erythrocytic development of theparasite, suppressive prophylaxis, i.e. antimalarial activity comprisingsuppressing the development of the blood stage infection and terminalprophylaxis, i.e. antimalarial activity comprising suppressing thedevelopment of intra-hepatic stage infection. This term includes primaryprophylaxis (i.e. preventing initial infection) where the antimalarialcompound is administered before, during and/or after the exposure periodto malarial parasites and terminal prophylaxis (i.e. to prevent relapsesor delayed onset of clinical symptoms of malaria) when the antimalarialcompound is administered towards the end of and/or slightly after theexposure period to malarial parasites but before the clinical symptoms.Typically, against P. falciparum infections, suppressive phophylaxis isused whereas against P. vivax or a combination of P. falciparum and P.vivax, terminal prophylaxis is used.

Likewise, the term “treatment-effective amount” refers to aconcentration of compound that is effective in treating malariainfection, e.g. leads to a reduction in parasite numbers in bloodfollowing microscopic examination when administered after infection hasoccurred.

The term “subject” as used herein refers to mammals. For examples,mammals contemplated by the present invention include humans and thelike. The compounds discussed herein in many instances may have beennamed and/or checked with ACD/Name by ACD/Labs® and/or Electronic LabNotebook by CambridgeSoft®.

Compounds of Formula (I) may form stable pharmaceutically acceptableacid or base salts, and in such cases administration of a compound as asalt may be appropriate. Examples of acid addition salts includeacetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate,bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate,cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate,glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate,lactate, malate, maleate, methanesulfonate, meglumine,2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate,phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate,quinate, salicylate, stearate, succinate, sulfamate, sulfanilate,sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, andundecanoate. Examples of base salts include ammonium salts; alkali metalsalts such as sodium, lithium and potassium salts; alkaline earth metalsalts such as aluminum, calcium and magnesium salts; salts with organicbases such as dicyclohexylamine salts and N-methyl-D-glucaminc; andsalts with amino acids such as arginine, lysine, ornithine, and soforth. Also, basic nitrogen-containing groups may be quaternized withsuch agents as: lower alkyl halides, such as methyl, ethyl, propyl, andbutyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl;diamyl sulfates; long chain halides such as decyl, lauryl, myristyl andstearyl halides; arylalkyl halides such as benzyl bromide and others.Non-toxic physiologically-acceptable salts are preferred, although othersalts may be useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water, which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion-exchange resin.

Compounds of Formula (I) have one or more chiral centres and/orgeometric isomeric centres, and it is to be understood that theinvention encompasses all such optical,diastereoisomers, and geometricisomers. The invention further relates to any and all tautomeric formsof the compounds of Formula (I).

It is also to be understood that certain compounds of Formula (I) canexist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms.

Additional embodiments of the invention are as follows. These additionalembodiments relate to compounds of Formula (I) and pharmaceuticallyacceptable salts thereof. Such specific substituents may be used, whereappropriate, with any of the definitions, claims or embodiments definedhereinbefore or hereinafter.

According to a particular aspect, is provided a compound of theinvention selected from the following group:

In another aspect, the present invention provides a compound selectedfrom:

N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-(4-methylpiperazin-1-yl)-N4-(1-methyltriazol-4-yl)pyrimidine-2,4-diamine;

N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-N4-(1,5-dimethylpyrazol-3-yl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-N4-(1-ethyl-5-methyl-pyrazol-3-yl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]-N4-(1-methyltriazol-4-yl)pyrimidine-2,4-diamine;

N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-N4-(1,5-dimethylpyrazol-3-yl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

4-cyclopropyl-6-[[4-[(1,5-dimethylpyrazol-3-yl)amino]-5-[3-methylpiperazin-1-yl]pyrimidin-2-yl]amino]-2-methyl-pyridine-3-carbonitrile;

N4-(1,5-dimethylpyrazol-3-yl)-N2-(4-ethyl-5-fluoro-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

N4-(1,5-dimethylpyrazol-3-yl)-N2-(4-ethyl-5-fluoro-6-methyl-2-pyridyl)-5-[(3S)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

N2-(4-cyclobutyl-5-fluoro-6-methyl-2-pyridyl)-N4-(1,5-dimethylpyrazol-3-yl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]-N4-(2-methyltriazol-4-yl)pyrimidine-2,4-diamine;

N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]-N4-(1-methyltriazol-4-yl)pyrimidine-2,4-diamine;

N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-5-[(3-methylpiperazin-1-yl]-N4-(2-methyltriazol-4-yl)pyrimidine-2,4-diamine;

N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[3,4-dimethylpiperazin-1-yl]-N4-(1,5-dimethylpyrazol-3-yl)pyrimidine-2,4-diamine;

N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[3,4-dimethylpiperazin-1-yl]-N4-(1-methyltriazol-4-yl)pyrimidine-2,4-diamine;and

N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[3,4-dimethylpiperazin-1-yl]-N4-(2-methyltriazol-4-yl)pyrimidine-2,4-diamine; as wellas pharmaceutically acceptable salts, complexes, hydrates, solvates,tautomers, polymorphs, racemic mixtures, optically active forms andpharmaceutically active derivative thereof.

According to a particular aspect, compounds of the invention areprovided as R enantiomers.

According to a particular aspect, compounds of the invention areprovided as S enantiomers or as a racemic mixture.

In another aspect, the present invention provides a compound selectedfrom:

Example 1:N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-(4-methylpiperazin-1-yl)-N4-(1-methyltriazol-4-yl)pyrimidine-2,4-diamine;

Example 2:N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-N4-(1,5-dimethylpyrazol-3-yl)-5-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

Example 3:N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-N4-(1-ethyl-5-methyl-pyrazol-3-yl)-5-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

Example 4:N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[(3R)-3-methylpiperazin-1-yl]-N4-(1-methyltriazol-4-yl)pyrimidine-2,4-diamine;

Example 5:N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-N4-(1,5-dimethylpyrazol-3-yl)-5-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

Example 6:4-cyclopropyl-6-[[4-[(1,5-dimethylpyrazol-3-yl)amino]-5-[(3R)-3-methylpiperazin-1-yl]pyrimidin-2-yl]amino]-2-methyl-pyridine-3-carbonitrile;

Example 7:N4-(1,5-dimethylpyrazol-3-yl)-N2-(4-ethyl-5-fluoro-6-methyl-2-pyridyl)-5-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

Example 8:N4-(1,5-dimethylpyrazol-3-yl)-N2-(4-ethyl-5-fluoro-6-methyl-2-pyridyl)-5-[(3S)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

Example 9:N2-(4-cyclobutyl-5-fluoro-6-methyl-2-pyridyl)-N4-(1,5-dimethylpyrazol-3-yl)-5-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;

Example 10:N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-5-[(3R)-3-methylpiperazin-1-yl]-N4-(2-methyltriazol-4-yl)pyrimidine-2,4-diamine;

Example 11:N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-5-[(3R)-3-methylpiperazin-1-yl]-N4-(1-methyltriazol-4-yl)pyrimidine-2,4-diamine;

Example 12:N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-5-[(3R)-3-methylpiperazin-1-yl]-N4-(2-methyltriazol-4-yl)pyrimidine-2,4-diamine;

Example 13:N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[(3R)-3,4-dimethylpiperazin-1-yl]-N4-(1,5-dimethylpyrazol-3-yl)pyrimidine-2,4-diamine;

Example 14:N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[(3R)-3,4-dimethylpiperazin-1-yl]-N4-(1-methyltriazol-4-yl)pyrimidine-2,4-diamine; and

Example 15:N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[(3R)-3,4-dimethylpiperazin-1-yl]-N4-(2-methyltriazol-4-yl)pyrimidine-2,4-diamine; as wellas pharmaceutically acceptable salts, complexes, hydrates, solvates,tautomers, polymorphs, racemic mixtures, optically active forms andpharmaceutically active derivative thereof.

According to a further particular embodiment, the present inventionprovides a compound selected fromN2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[3,4-dimethylpiperazin-1-yl]-N4-(1,5-dimethylpyrazol-3-yl)pyrimidine-2,4-diamine andits active metaboliteN2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-N4-(1,5-dimethylpyrazol-3-yl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine.

According to another further particular embodiment, the presentinvention provides a compoundN4-(1,5-dimethylpyrazol-3-yl)-N2-(4-ethyl-5-fluoro-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine.

According to another further particular embodiment, the presentinvention provides a compoundN2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]-N4-(2-methyltriazol-4-yl)pyrimidine-2,4-diamine.

Thus, in one aspect there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use as a medicament.

The compounds according to the invention may thus be used for thepreparation of medicaments, in particular medicaments for inhibitingparasite growth.

Thus, according to another of its aspects, a subject of the invention ismedicaments that comprise a compound of formula (I), or an addition saltof the compound of formula (I) with a pharmaceutically acceptable acidor base.

These medicaments find their use in therapeutics, especially in thetreatment of malaria caused by all species of plasmodium such as P.falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi.

Accordingly, in one aspect, there is provided the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a parasitic infectioncaused by plasmodium species in a warm-blooded animal such as humanbeing.

In another aspect, there is provided the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for the production of an antimalarial effect in awarm-blooded animal such as human being.

In another aspect, there is provided a method for treating a parasiticinfections caused by plasmodium species in a warm-blooded animal such ashuman being, said method including administering to said animal aneffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof.

In another aspect, there is provided a method for producing ananti-malaria effect in a warm-blooded animal such as human being, saidmethod including administering to said animal an effective amount of acompound of formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatmentand/or prophylaxis of malaria in a warm-blooded animal, such as humanbeing.

A compound of Formula (I), or a pharmaceutically acceptable saltthereof, for the therapeutic and prophylactic treatment of mammalsincluding humans, in particular in treating malaria caused by plasmodiumspecies, is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

Accordingly, in one aspect, there is provided a pharmaceuticalcomposition including a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier, diluent, or excipient.

In another aspect, there is provided the use of a pharmaceuticalcomposition including a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for thetreatment of a parasitic infection caused by plasmodium species in awarm-blooded animal such as human being.

In another aspect, there is provided the use of a pharmaceuticalcomposition including a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for theproduction of an antimalarial effect in a warm-blooded animal such ashuman being.

In another aspect, there is provided a method for treating malariacaused by plasmodium species in a warm-blooded animal such as humanbeing, said method including administering to said animal an effectiveamount of a pharmaceutical composition including a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

In another aspect, there is provided a method for producing ananti-malarial effect in a warm-blooded animal such as human being, saidmethod including administering to said animal an effective amount of apharmaceutical composition including a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In another aspect, there is provided a pharmaceutical compositionincluding a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, for use in treating malaria caused by plasmodium speciesin a warm-blooded animal, such as human being.

In another aspect, there is provided a pharmaceutical compositionincluding a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, for use in the production of an anti-malarial effect in awarm-blooded animal, such as human being.

Pharmaceutical Compositions

In some aspects, the invention provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable diluent or carrier.

The language “pharmaceutically acceptable” includes compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The compounds of formula (I) may form stable pharmaceutically acceptableacid or base salts, and in such cases administration of a compound as asalt may be appropriate. Examples of acid addition salts includeacetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate,bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate,cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate,glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate,lactate, malate, maleate, methanesulfonate, meglumine,2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate,phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate,quinate, salicylate, stearate, succinate, sulfamate, sulfanilate,sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, andundecanoate. Examples of base salts include ammonium salts; alkali metalsalts such as sodium, lithium and potassium salts; alkaline earth metalsalts such as aluminum, calcium and magnesium salts; salts with organicbases such as dicyclohexylamine salts and N10 methyl-D-glucamine; andsalts with amino acids such as arginine, lysine, ornithine, and soforth. Also, basic nitrogen-containing groups may be quaternized withsuch agents as: lower alkyl halides, such as methyl, ethyl, propyl, andbutyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl;diamyl sulfates; long chain halides such as decyl, lauryl, myristyl andstearyl halides; arylalkyl halides such as benzyl bromide and others.Non-toxic physiologically acceptable salts are preferred, although othersalts may be useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water, which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion-exchange resin.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more coloring, sweetening, flavoring and/or preservativeagents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate; granulating and disintegratingagents such as corn starch or algenic acid, potato starch orsodiumstarch glycollate; binding agents such as starch; lubricating agentssuch as magnesium stearate, stearic acid or talc, polyethylene glycol,and silica; preservative agents such as ethyl or propylp-hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tabletformulations may be uncoated or coated either to modify theirdisintegration and the subsequent absorption of the active ingredientwithin the gastrointestinal tract, or to improve their stability and/orappearance, in either case, using conventional coating agents andprocedures well known in the art.

For example, tablets and capsules for oral administration may furthercontain conventional excipients including, but not limited to, fillers,disintegrants and wetting agents. Fillers include, but are not limitedto, lactose, sugar, microcrystalline cellulose, maizestarch, calciumphosphate, and sorbitol.

Binding agents include, but are not limited to, syrup, accacia, gelatin,sorbitol, tragacanth, mucilage of starch and polyvinylpyrrolidone.

Tablets may be coated according to methods well known in the art. Forexample, tablets and capsules for oral administration may containconventional excipients including, but not limited to, binding agents,fillers, lubricants, disintegrants and wetting agents. Compositions fororal use may be in the form of hard gelatin capsules in which the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsules inwhich the active ingredient is mixed with water or an oil such as peanutoil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form or in the form of nano or micronized particles togetherwith one or more suspending agents, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as lecithin or condensation productsof an alkylene oxide with fatty acids (for example polyoxethylenestearate), or condensation products of ethylene oxide with long chainaliphatic alcohols, for example heptadecaethyleneoxycetanol, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and a hexitol such as polyoxyethylene sorbitol monooleate,or condensation products of ethylene oxide with long chain aliphaticalcohols, for example heptadecaethyleneoxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol such as polyoxyethylene sorbitol monooleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives such as ethyl or propyl p-hydroxybenzoate; anti-oxidantssuch as ascorbic acid); coloring agents; flavoring agents; and/orsweetening agents such as sucrose, saccharine or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as arachis oil, olive oil, sesame oil or coconutoil or in a mineral oil such as liquid paraffin. The oily suspensionsmay also contain a thickening agent such as beeswax, hard paraffin orcetyl alcohol. Sweetening agents such as those set out above, andflavoring agents may be added to provide a palatable oral preparation.These compositions may be preserved by the addition of an anti-oxidantsuch as ascorbic acid. Dispersible powders and granules suitable forpreparation of an aqueous suspension by the addition of water generallycontain the active ingredient together with a dispersing or wettingagent, suspending agent and one or more preservatives. Suitabledispersing or wetting agents and suspending agents are exemplified bythose already mentioned above. Additional excipients such as sweetening,flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient. Compositions for administration may also be formulated as aliosome preparation. The liposome preparation can comprise liposomeswhich penerate the cells of interest or stratum corneum, and fuse withthe cell membrane, resulting in delivery of the contents of the liposomeinto the cell. Other suitable formulations can employ niosomes. Niosomesare lipd vesicles similar to liposomes, with membrane consisting largelyof nonoinic lipids,some forms of which are effective for transportingcompounds across the stratum corneum.

Compositions for administration may also be formulated as a depotpreparation, which may administered by implantation or by intramuscularinjection. The compositions may be formulated with suitable polymeric orhydrophobic material (as an emulsion in acceptable oil), ion exchangeresins, or sparingly soluble derivatives.

The compound of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems.

For further information on formulation, drug delivery as well asprocessing techniques the reader is referred to Remington'sPharmaceutical Sciences (21st Edition, 2005, University of the sciencesin Philadelphia, Lippincott William & Wilkins or in The Science andPractice of Pharmacy (Remington: The Science & Practice of Pharmacy),22^(nd) Edition, 2012, Lloyd, Ed. Allen, Pharmaceutical Press which isincorporated herein by reference).

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 4 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990 and Remington's Pharmaceutical Sciences, supra).

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular disease state will necessarily bevaried depending on the host treated, the route of administration andthe severity of the illness being treated. Preferably a daily dose inthe range of 1-25 mg/kg is employed. Accordingly, the optimum dosage maybe determined by the practitioner who is treating any particularpatient.

In any of the pharmaceutical compositions, processes, methods, uses,medicaments, and manufacturing features mentioned herein, any of thealternate aspects of the compounds of the invention described hereinalso apply.

Route of Administration

Compositions of this invention may be administered in any manner,including, but not limited to, orally, parenterally,sublingually,transdermally, vaginally, rectally, transmucosally,topically, via inhalation, via buccal or intranasal administration, orcombinations thereof. The compositions of this invention may also beadministered in the form of an implant, which allows the slow release ofthe compositions as well as slow controlled i.v. infusion. In aprerefered embodiment, triaminopyrimidine derivatives according to theinvention are administered orally.

In a particular embodiment, compounds of the invention are administeredat a dose to humans of between about 1 mg and 1,500 mg such as forexample at about 200 to 700 mg. In a further particular embodiment,compound of the invention are administered at a dose of less than 600 mg(e.g. from about 260 mg to about 520 mg). This invention is furtherillustrated by the following examples that are not intended to limit thescope of the invention in any way.

The dosage administered, as single or multiple, to an individual willvary depending upon a variety of factors, including the pharmacokineticproperties, patient conditions and characteristics (sex, age, body,weight, health, size), extent of symptoms, concurrent treatmentsfrequency of treatment and the effect desired.

Combinations

The compounds of the invention described herein may be applied as a soletherapy or may involve, in addition to a compound of the invention, oneor more other substances and/or treatments. Such co-treatment may beachieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the beneficial effect ofthe combination.

According to a particular embodiment of the invention, the compounds ofthe invention and pharmaceutical formulations thereof can beadministered in combination with a co-agent useful in the treatment ofmalaria.

Suitable classes and substances include one or more antimalarial agentsuseful in the treatment and prevention of malaria such as, for example,artemisinin or an artimisinin derivative (such as artemether ordihydroartemisinin), chloroquinine, mefloquine, quinine,atoquone/proguanil, doxycycline, hydroxychloroquinine, halofantrine,pyronaridine, lumefantrine, pyrmethamine-sulfadoxine and piperaquine.

Are also included, amodiaquine, atovaquone, proguanil hydrochloride,Spiro[3H-indole-3,1′-[1H]pyrido[3,4-b]indol]-2(1H)-one (CAS RegistryNumber: 1193314-23-6),5,7′-dichloro-6′-fluoro-2′,3′,4′,9′-tetrahydro-3′-methyl-,(1′R,3′S)-],Sulfur,[4-[[2-(1,1-difluoroethyl)-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]amino]phenyl]pentafluoro-](CAS Registry Number: 1282041-94-4), Morpholine, and4-[2-(4-cis-dispiro[cyclohexane-1,3′-[1,2,4]trioxolane-5′,2″-tricyclo[3.3.1.13,7]decan]-4-ylphenoxy)ethyl]-] (CAS Registry Number: 1029939-86-3).

Further co-agent useful in the context of the invention are selectedfrom quinacrine, primaquine, tafenaquine, doxycycline, ferroquine, andarterolane.

The invention encompasses the administration of at least one compound ofthe invention according to the invention or of a pharmaceuticalformulation thereof, wherein the compound of the invention or thepharmaceutical formulation thereof is administered to an individualprior to, simultaneously or sequentially with other therapeutic regimensor co-agents useful in the treatment of malaria (e.g. multiple drugregimens), in an effective amount. Compound of the invention or thepharmaceutical formulations thereof that are administered simultaneouslywith said co-agents can be administered in the same or differentcomposition(s) and by the same or different route(s) of administration.

Patients

In an embodiment, patients according to the invention are suffering frommalaria. In another embodiment, patients according to the invention arepatients with a high risk of being infected by Plasmodium.

In another embodiment, patients according to the invention are patientswith a high risk of being infected by Plasmodium falciparum.

In another embodiment, patients according to the invention are patientswith a high risk of being infected by Plasmodium vivax.

Use According to the Invention

In one embodiment, the invention provides a use of a compound accordingto Formula (I) as described herein, as well pharmaceutically acceptablesalt, hydrate, solvate, polymorph, tautomers, geometrical isomers, oroptically active forms thereof for the preparation of a pharmaceuticalcomposition for the treatment or prophylaxis of malaria.

In another embodiment, the invention provides a method for preventing ortreating malaria in a patient. The method comprises administering aneffective amount of a compound according to the invention, or apharmaceutically acceptable salt or a pharmaceutically active derivativethereof or a pharmaceutical formulation thereof in a patient in needthereof.

In another embodiment, the invention provides a compound according tothe invention as well as pharmaceutically acceptable salts or apharmaceutically active derivative thereof or a pharmaceuticalformulation thereof, for use in the treatment or prophylaxis of malaria.

In another embodiment, the invention provides a use of a compound of theinvention or a method according to the invention wherein the compound ofthe invention is to be administered in combination with a co-agentuseful in the treatment of malaria.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a compound of the invention according to theinvention in combination with a co-agent useful in the treatment ofmalaria.

The compounds and compositions of this invention may be used in a methodfor inactivating parasitic infection in a cell comprising the step ofcontacting the cell with an effective amount of at least one compoundaccording to the invention. According to a particular aspect, the cellis a primate cell such as a red blood cell for example a human cell.

Process

In another embodiment, the invention provides a process for thepreparation of an compound of Formula (I) comprising the step ofreacting a derivative according to Formula (IV) with a derivative ofFormula (V) to lead to an intermediate of Formula (X) under palladiumcatalysed amination conditions (e.g. using9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene andTris(dibenzylideneacetone) dipalladium as catalyst) as follows:

wherein R is a protecting group (e.g. Boc).

In another embodiment, the invention provides a process for thepreparation of a compound of Formula (I) comprising the step of reactinga derivative according to Formula (X) to lead to a compound of Formula(I) under acidic conditions (e.g. 4N hydrochloric acid or trifluoroacetic acid) as follows below.

Wherein R is a protecting group (e.g. Boc).

In a further optional step the compounds of Formula (I) where R₆=H arefurther converted under reductive amination conditions to a furthercompound of Formula (I) wherein R⁶=alkyl.

In another embodiment, the invention provides a process for thepreparation of an compound of Formula (I) comprising the step ofreacting a derivative according to Formula (IV) with a derivative ofFormula (V) to lead to an intermediate of Formula (X) under palladiumcatalysed amination conditions (e.g. using9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene andTris(dibenzylideneacetone) dipalladium as catalyst) as follows:

wherein R is R⁶ and R⁶ is alkyl.

In another embodiment, the invention provides an intermediate of Formula(IV) wherein R⁴, R⁵ and HAR are as defined herein and R is selected froma protecting group (e.g. Boc) and R⁶:

In another embodiment, the invention provides an intermediate of Formula(IV) selected from the following group:

tert-butyl4-(2-chloro-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(2-chloro-4-((1-ethyl-5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(2-chloro-4-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(2-chloro-4-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;and

2-chloro-N-(1-methyl-1H-1,2,3-triazol-4-yl)-5-(4-methylpiperazin-1-yl)pyrimidin-4-amine.

In another embodiment, the invention provides an intermediate of Formula(X) wherein R¹, R², R³ R⁴, R⁵ and HAR are as defined herein and R is aprotecting group (e.g. Boc):

In another embodiment, the invention provides an intermediate of Formula(X) selected from the following group:

tert-butyl4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((1-ethyl-5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(2-((5-chloro-4-cyclopropyl-6-methylpyridin-2-yl)amino)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(2-((5-cyano-4-cyclopropyl-6-methylpyridin-2-yl)amino)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-2-((4-ethyl-5-fluoro-6-methylpyridin-2-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-2-((4-ethyl-5-fluoro-6-methylpyridin-2-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(2-((4-cyclobutyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(2-((5-chloro-4-cyclopropyl-6-methylpyridin-2-yl)amino)-4-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;

tert-butyl4-(2-((5-chloro-4-cyclopropyl-6-methylpyridin-2-yl)amino)-4-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate;and

tert-butyl4-(2-((3-cyclopropyl-4-fluoro-5-methylphenyl)amino)-4-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate.

If not commercially available, the necessary starting materials for theprocedures such as those described herein may be made by procedureswhich are selected from standard organic chemical techniques, techniqueswhich are analogous to the synthesis of known, structurally similarcompounds, or techniques which are analogous to the described procedureor the procedures described in the Examples.

It is noted that many of the starting materials for synthetic methods asdescribed herein are commercially available and/or widely reported inthe scientific literature, or could be made from commercially availablecompounds using adaptations of processes reported in the scientificliterature. The reader is further referred to Advanced OrganicChemistry, 5^(th) Edition, by Jerry March and Michael Smith, publishedby John Wiley & Sons 2001, for general guidance on reaction conditionsand reagents.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups incompounds. The instances where protection is necessary or desirable areknown to those skilled in the art, as are suitable methods for suchprotection. Conventional protecting groups may be used in accordancewith standard practice (for illustration see T. W. Greene, ProtectiveGroups in Organic Synthesis, published by John Wiley and Sons, 1991) andas described hereinabove.

EXAMPLES

The invention is now illustrated by, but not limited to, the followingExamples, for which, unless otherwise stated:

-   (i) evaporations were carried out by rotary evaporation in vacuo and    work-up procedures were carried out after removal of residual solids    by filtration;-   (ii) temperatures are quoted as ° C.; operations were carried out at    room temperature, that is typically in the range 18-26° C. and    without the exclusion of air unless otherwise stated, or unless the    skilled person would otherwise work under an inert atmosphere;-   (iii) column chromatography (by the flash procedure) was used to    purify compounds and was performed on Merck Kieselgel silica    (Art. 9385) unless otherwise stated;-   (iv) in general, the course of reactions was followed by TLC, HPLC,    or LC/MS and reaction times are given for illustration only; yields    are given for illustration only and are not necessarily the maximum    attainable;-   (v) the structure of the end-products of the invention was generally    confirmed by NMR and mass spectral techniques. Proton magnetic    resonance spectra were generally determined in DMSO-d₆ unless    otherwise stated, using a Bruker DRX-300 spectrometer or a Bruker    DRX-400 spectrometer, operating at a field strength of 300 MHz, or    400 MHz, respectively. In cases where the NMR spectrum is complex,    only diagnostic signals are reported. Chemical shifts are reported    in parts per million downfield from tetramethylsilane as an external    standard (δ scale) and peak multiplicities are shown thus: s,    singlet; d, doublet; dd, doublet of doublets; dt, doublet of    triplets; dm, doublet of multiplets; t, triplet, m, multiplet; br,    broad. Fast-atom bombardment (FAB) mass spectral data were generally    obtained using a Platform spectrometer (supplied by Micromass) run    in electrospray and, where appropriate, either positive ion data or    negative ion data were collected or using Agilent 1100 series LC/MS    equipped with Sedex 75ELSD, and where appropriate, either positive    ion data or negative ion data were collected. The lowest mass major    ion is reported for molecules where isotope splitting results in    multiple mass spectral peaks (for example when chlorine is present).    Reverse Phase HPLC was carried out using YMC Pack ODS-AQ (100×20    mmID, S-5μ particle size, 12 nm pore size) on Agilent instruments;-   (vi) each intermediate was purified to the standard required for the    subsequent stage and was characterized in sufficient detail to    confirm that the assigned structure was correct; purity was assessed    by HPLC, TLC, or NMR and identity was determined by infra-red    spectroscopy (IR), mass spectroscopy or NMR spectroscopy as    appropriate; and-   (vii) the following abbreviations may be used:

ACN—acetonitrile; TLC—thin layer chromatography; HPLC—high pressureliquid chromatography; MPLC—medium pressure liquid chromatography;NMR—nuclear magnetic resonance spectroscopy; DMADimethylacetamide-DMSO—dimethylsulfoxide; CDCl₃—deuterated chloroform;MeOD—deuterated methanol, i.e. D₃COD; MS—mass spectroscopy; ESP (orES)—electrospray; HBSS—Hank's balanced salt solution; EI—electronimpact; APCI—atmospheric pressure chemical ionization;THF—tetrahydrofuran; DCM—dichloromethane; HPMC—HydroxypropylMethylcellulose; MeOH—methanol; DMF—dimethylformamide; EtOAc—ethylacetate; LC/MS—liquid chromatography/mass spectrometry; h—hour(s); minis minute(s); d—day(s);MTBD—N-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene; NADPH—Nicotinamideadenine dinucleotide phosphate—reduced form; PEG—Polyethylene Glycol;RT—room temperature; TEER—Trans epithelial electric resistance;TFA—trifluoroacetic acid; v/v—ratio of volume/volume; Boc denotest-butoxycarbonyl; Cbz denotes benzyloxycarbonyl; Bz denotes benzoyl; atmdenotes atmospheric pressure; rt denotes room temperature; mg denotesmilligram; g denotes gram; μL denotes microliter; mL denotes milliliter;L denotes liter; μM denotes micromolar; mM denotes millimolar; M denotesmolar; N denotes normal; nm denotes nanometer.

In accordance with the invention, the compounds of generic formula (I)may be prepared according to the processes that follow. The synthesis ofthe intermediates (II-Xk) and compounds of generic formula (I) aredescribed in Scheme 1, 2 and 3.

Intermediate II(R)-tert-butyl-4-(2,4-dioxo-1,2,3,4-tetrahvdropyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

In a Biotage microwave vial, 5-bromopyrimidine-2,4(1H,3H)-dione (Ia) (24g, 125.67 mmol, Aldrich) and (R)-tert-butyl2-methylpiperazine-1-carboxylate (37.8 g, 188.50 mmol, ActivateScientific) were taken in pyridine (12 mL) and irradiated at 150° C. for90 min. Pyridine was removed under vacuum and residue was poured inwater to get the suspension, which was filtered and vacuum dried to getsolid of(R)-tert-butyl-4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methylpiperazine-1-carboxylate(22.00 g, 56.4%). Note: Reaction was done in 12 batches of 2 g each. Allcombined and work up was done. ¹H NMR (300 MHz, DMSO-J6) δ ppm 1.19 (d,J=6.78 Hz, 3 H) 1.40 (s, 9 H) 2.30 (d, J=2.83 Hz, 1 H) 2.42 (dd,J=11.30, 3.58 Hz, 1 H) 2.93-3.22 (m, 3 H) 3.72 (d, J=13.19 Hz, 1 H) 4.12(br. s., 1 H) 6.73 (d, J=4.71 Hz, 1 H) 10.51 (br. s., 1 H) 11.10 (s, 1H) MS (ES⁺), (M+H)⁺=310.09 for C₁₄H₂₂N₄O₄.

Intermediate IIa(S)-tert-butyl-4-(2,4-dioxo-1,2,3,4-tetrahvdropyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

Intermediate IIa was prepared from 5-bromopyrimidine-2,4(1H,3H)-dione(Aldrich) and (S)-tert-butyl 2-methylpiperazine-1-carboxylate(ActivateScientific) using procedure analogous to intermediate II. ¹H NMR (300MHz, DMSO-J6) δ ppm 1.19 (d, J=6.78 Hz, 3 H) 1.40 (s, 9 H) 2.30 (d,J=2.83 Hz, 1 H) 2.42 (dd, J=11.30, 3.58 Hz, 1 H) 2.93-3.22 (m, 3 H) 3.72(d, J=13.19 Hz, 1 H) 4.12 (br. s., 1 H) 6.73 (d, J=4.71 Hz, 1 H) 10.51(br. s., 1 H) 11.10 (s, 1 H) MS (ES⁺), (M+H)⁺=310.09 for C₁₄H₂₂N₄O₄.

Intermediate III (R)-tert-butyl4-(2,4-dichloropyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

In a 2L round-bottomed flask, (R)-tert-butyl4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methylpiperazine-1-carboxylate(22 g, 70.89 mmol, Intermediate II) taken in phosphorus oxychloride (793ml, 8506.56 mmol) to give a brown suspension. The reaction mixture wasrefluxed for 5-6 h, reaction was monitored by LCMS and identified therequired mass. Phosphorus oxychloride was distilled out under reducedpressure, the remaining oil was diluted with THF (250 mL) and crushedice 400 g), the reaction mixture was basified to pH 8. To this was addedDi-tert-butyl dicarbonate (22.17 ml, 96.41 mmol, Aldrich) was added tothe mixture and stirred for 16 h at rt. The reaction mixture was dilutedwith methanol and filtered it off to remove excess salt. The solvent wasremoved under vacuum and residue was diluted with water (50 mL) andextracted with ethyl acetate (500 mL×3). Organic layers were dried oversodium sulphate and solvent was removed under reduced pressure. Theresidue was loaded on silica gel and purified to obtain solid of(R)-tert-butyl4-(2,4-dichloropyrimidin-5-yl)-2-methylpiperazine-1-carboxylate (23.00g, 93%) ¹H NMR (300 MHz, CDCl₃) δ ppm 1.31 (d, J=6.78 Hz, 3 H) 1.37-1.47(m, 9 H) 2.70-2.93 (m, 2 H) 3.15-3.29 (m, 3 H) 3.94 (d, J=13.94 Hz, 1 H)4.33 (br. s., 1 H) 8.11 (s, 1 H) MS (ES⁺), (M+H)⁺=349 for C₁₄H₂₀Cl₂N₄O₂.

Intermediate IIIa (S)-tert-butyl4-(2,4-dichloropyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

Intermediate IIIa was prepared from IIa using procedure analogous tointermediate III. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.31 (d, J=6.78 Hz, 3 H)1.37-1.47 (m, 9 H) 2.70-2.93 (m, 2 H) 3.15-3.29 (m, 3 H) 3.94 (d/=13.94Hz, 1 H) 4.33 (br. s., 1 H) 8.11 (s, 1 H) MS (ES⁺), (M+H)⁺=349 forC₁₄H₂₀Cl₂N₄O₂.

Intermediate IVa (R)-tert-butyl4-(2-chloro-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

In a 25 mL Biotage microwave vial (R)-tert-butyl4-(2,4-dichloropyrimidin-5-yl)-2-methylpiperazine-1-carboxylate (500 mg,1.44 mmol, Intermediate III) and 1,5-dimethyl-1H-pyrazol-3-amine (160mg, 1.44 mmol, Princeton Bio.) was taken in ethanol (10 mL).N,N-diisopropylethylamine (0.754 mL, 4.32 mmol) was added and thereaction mass was subjected to microwave irradiation at 120° C. for 4hours. The reaction was monitored by LCMS and identified the requiredmass. Reaction mass was cooled and evaporated to dryness and the residuewas then chromatographed with EtoAc/Hexane on silica to get pure solidof (R)-tert-butyl4-(2-chloro-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate (300 mg, 49.4 %) MS (ES⁺), (M+H)⁺=422.20 forC₁₉H₂₈ClN₇O₂

Intermediate IVb (R)-tert-butyl4-(2-chloro-4-((1-ethyl-5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

Intermediate IVb was prepared from 1-ethyl,5-methyl-1H-pyrazol-3-amine(ChemCollect) and Intermediate III using procedure analogous tointermediate IVa. Yield: 63.7%, MS (ES⁺), (M+H)⁺=436.38 forC₂₀H₃₀ClN₇O₂.

Intermediate IVc (R)-tert-butyl4-(2-chloro-4-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

In a 50 ml round bottom flask 2-methyl-2H-1,2,3-triazol-4-aminehydrochloride (388 mg, 2.88 mmol, ChemBridge) was taken in DCM (2 mL)and Triethyl amine (200 mL, 1.44 mmol) was added under ice cooling andstirred for 5 min. This was evaporated completely to dryness. Residuewas dissolved in DMF (10 mL) and cooled using ice bath. Sodium hydride(173 mg, 4.32 mmol) was added and stirred at cold for 15 mins and(R)-tert-butyl4-(2,4-dichloropyrimidin-5-yl)-2-methylpiperazine-1-carboxylate (500 mg,1.44 mmol, Intermediate III) was added. The resulting reaction mixturewas stirred at RT for overnight. Reaction was followed by LCMS andidentified required mass. DMF was evaporated and the suspension was thenpartitioned between water and ethyl acetate. Organic layers werecombined, dried over sodium sulphate, concentrated to dryness andpurified on combiflash to get (R)-tert-butyl4-(2-chloro-4-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate(180 mg, 30.6%). MS (ES⁺), (M+H)⁺=409.36 for C₁₇H₂₅ClN₈O₂.

Intermediate IVd (R)-tert-butyl4-(2-chloro-4-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

Intermediate IVd was prepared from 1-methyl-1H-1,2,3-triazol-4-aminehydrochloride (ChemBridge) and Intermediate III using procedureanalogous to intermediate IVc Yield: 51%. MS (ES⁺), (M+H)⁺=409.32 forC₁₇H₂₅ClN₈O₂.

Intermediate IVe (S)-tert-butyl4-(2-chloro-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

Intermediate IVe was prepared from 1,5-dimethyl-1H-pyrazol-3-amine (160mg, 1.44 mmol, Princeton Bio.) and Intermediate Ilia using procedureanalogous to intermediate Iva. Yield: 49%, MS (ES⁺), (M+H)⁺=422.20 forC₁₉H₂₈ClN₇O₂.

Intermediate IIb 5-(4-methylpiperazin-1-yl)pyrimidine-2,4(1H,3H)-dione

In a 20 mL Biotage microwave vial 5-Bromouracil (3 g, 15.71 mmol,Aldrich) and N-methylpiperazine (2.61 mL, 23.56 mmol, Aldrich) weretaken in pyridine (15 mL) to give a white suspension. The vial was thencapped and subjected to microwave irradiation for 45 mins at 150° C. .The reaction was monitored by LCMS and identified the required mass.Pyridine was removed under vacuum and the residue was then trituratedwith ethyl acetate and the suspension was filtered off and vacuum driedto get 5-(4-methylpiperazin-1-yl) pyrimidine-2,4(1H,3H)-dione (3.30 g,100 %) as a dark grey solid. ¹H NMR (300 MHz, DMSO-d6) δ ppm 2.07 (s, 3H) 2.43-2.49 (m, 4 H) 2.98-3.09 (m, 4 H) 7.21 (s, 1H) 10.84 (br. s., 1H)MS (ES⁺), (M+H)⁺=211.09 for C₉H₁₄N₄O₂.

Intermediate IIIb 2,4-dichloro-5-(4-methylpiperazin-1-yl)pyrimidine

In a 250 mL two neck round-bottomed flask5-(4-methylpiperazin-1-yl)pyrimidine-2,4(1H,3H)-dione (3.30 g, 15.70mmol, Intermediate IIb) was taken in phosphorus oxychloride (200 ml,2145.67 mmol) to give a brown suspension. The reaction mass was thenheated to 120° C. for 4 hrs. The reaction was monitored by LCMS andidentified required mass. Phosphorus oxychloride was evaporated undervacuum to get a thick dark residue. Ice was added to it and wasneutralized with sodium bicarbonate to pH 8 under cooling. Thesuspension was then extracted with 10% Methanol in dichloromethane. Theorganic layer was dried over sodium sulphate and solvent was removedunder vacuum to get residue, which was purified on combiflash withMethanol and dichloromethane to get solid of2,4-dichloro-5-(4-methylpiperazin-1-yl)pyrimidine (1.100 g, 28.4 %). ¹HNMR (300 MHz, CDCl₃) δ ppm 2.34-2.38 (s, 3H) 2.52-2.63 (m, 4 H) 3.13(br. s., 4 H) 8.64 (s, 1H) MS (ES⁺), (M+H)⁺=247 for C₉H₁₂C₁₂N₄.

Intermediate IVf2-chloro-N-(1-methyl-1H-1,2,3-triazol-4-yl)-5-(4-methylpiperazin-1-yl)pyrimidin-4-amine

Intermediate IVf was prepared from 1-methyl-1H-1,2,3-triazol-4-aminehydrochloride (ChemBridge) and Intermediate IIIb using procedureanalogous to intermediate IVc. Yield: 29.5%. MS (ES⁺), (M+H)⁺=309.32 forC₁₂H₁₅ClN₈.

Intermediate Va 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine

In a 100 ml three necked round bottom flask equipped with condenser andthermometer, solution of sulfuric acid (1.318 mL, 24.73 mmol) in water(45 mL) was taken and to this cyclopropanecarboxylic acid (2.129 g,24.73 mmol, Aldrich), Silver nitrate (1.260 g, 7.42 mmol) were added. Tothe resultant suspension 6-chloro-3-fluoro-2-methylpyridine (1.8 g,12.37 mmol, Matrix Scientific) was added to give a white suspension. Themixture was heated to 70° C. and then freshly prepared Ammoniumpersulfate (8.47 g, 37.10 mmol) solution in water (35 mL) was added dropwise for 20 min. After completion of addition, heating source wasremoved and kept for carbon dioxide evolution. The reaction wasmonitored by TLC. Then mixture was cooled and work up with sodiumbicarbonate to the neutral pH and the compound was extracted intodiethyl ether (3×50 ml).organic layer was evaporated to obtain crudesample 2.1 g. The crude sample was purified on silica gel usingDCM-Hexane to obtain 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine(0.540 g, 23.53 %) ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.87-0.95 (m, 2 H)1.05-1.15 (m, 2 H) 2.00-2.12 (m, 1 H) 2.38 (d, J=3.20 Hz, 3 H) 6.96 (d,J=4.71 Hz, 1 H) MS (ES⁺), (M+H)⁺=186.05 for C₉H₉ClFN.

Intermediate Vb4-cyclopropyl-N-(diphenylmethylene)-5-fluoro-6-methylpyridin-2-amine

6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine (Intermediate Va, 532mg, 2.87 mmol) was taken in a 25 ml thermal reactor and was dissolved inToluene (10 mL). Benzenemethanimine, alpha-phenyl-(0.721 mL, 4.30 mmol,Aldrich), racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (71.4 mg,0.11 mmol, Aldrich), Palladium (II) acetate (25.7 mg, 0.11 mmol,Aldrich) and Cesium carbonate (1401 mg, 4.30 mmol) were added into thisand the resulting mixtures was refluxed at 120° C. under nitrogen forovernight. Reaction was monitored with LCMS showed product formation.Resultant mass was concentrated and purified over combiflash followed bygilson HPLC to get pure yellow gum of4-cyclopropyl-N-(diphenylmethylene)-5-fluoro-6-methylpyridin-2-amine(350 mg, 37.0%) ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.44-0.55 (m, 2 H)0.82-1.02 (m, 2 H) 1.81-1.96 (m, 1 H) 2.25 (d, J=3.20 Hz, 3 H) 5.98 (d,J=4.90 Hz, 1 H) 7.10 (dd, J=6.59, 2.83 Hz, 2 H) 7.28-7.37 (m, 3 H)7.44-7.60 (m, 3 H) 7.62-7.71 (m, 2 H) MS (ES⁺), (M+H)⁺=331.40 forC₂₂Hl₉FN₂.

Intermediate V 4-cyclopropyl-5-fluoro-6-methylpyridin-2-aminehydrochloride

In a 50 mL round-bottomed flask4-cyclopropyl-N-(diphenylmethylene)-5-fluoro-6-methylpyridin-2-amine(350 mg, 1.06 mmol) was taken in 1,4-dioxane (10 mL) colorless solution.HCl in Dioxane (4 ml, 16.00 mmol) was added slowly at rt. Reaction masswas stirred at RT for 2 h shows reaction completed which is confirmed byLCMS. Reaction mass was concentrated and triturated with acetonitrile toget white solid of 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine (200mg, 93 %) as a hydrochloride salt. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.77-0.92 (m, 2 H) 1.14-1.27 (m, 2 H) 1.97-2.18 (m, 1H) 2.37 (d, J=3.01Hz, 3 H) 6.33 (d, J=5.84 Hz, 1H) 7.49 (br. s., 2 H) 14.19 (br. s., 1H)MS (ES⁺), (M+H)⁺=167.12 for C₉H₁₁FN₂,

Intermediate VIa 6-chloro-4-ethyl-3-fluoro-2-methylpyridine

Intermediate VIa was prepared from 6-chloro-3-fluoro-2-methylpyridine(Matrix Scientific) and propionic acid using procedure analogous tointermediate Va. Yield: 50.5% ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.18 (t,J=7.54 Hz, 3 H) 2.26 (d, J=1.13 Hz, 3 H) 2.63-2.81 (m, 2 H) 7.36 (d,J=4.71 Hz, 1 H). MS (ES⁺), (M+H)⁺=174.12 for C₈H₉ClFN.

Intermediate VIbN-(diphenylmethylene)-4-ethyl-5-fluoro-6-methylpyridin-2-amine

Intermediate VIb was prepared from Intermediate Via using procedureanalogous to intermediate Vb. Yield: 28% ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.18 (t, J=7.54 Hz, 3 H) 2.26 (d, J=1.13 Hz, 3 H) 2.63-2.81 (m, 2 H)5.98 (d, J=4.90 Hz, 1 H) 7.10 (dd, J=6.59, 2.83 Hz, 2 H) 7.28-7.37 (m, 3H) 7.44-7.60 (m, 3 H) 7.62-7.71 (m, 2 H) MS (ES⁺), (M+H)⁺=319.12 forC₂₁H₁₉FN₂.

Intermediate VI 4-ethyl-5-fluoro-6-methylpyridin-2-amine hydrochloride

Intermediate VI was prepared from Intermediate Vlb using procedureanalogous to intermediate V. Yield: 94%/H NMR (300 MHz, DMSO-d₆) δ ppm1.18 (t, J=7.54 Hz, 3 H) 2.26 (d, J=1.13 Hz, 3 H) 2.63-2.81 (m, 2 H)7.36 (d, J=4.71 Hz, 1 H). MS (ES⁺), (M+H)⁺=155.06 for C₈H₁₁FN₂.

Intermediate VIIa 6-chloro-4-cyclopropyl-2-methylnicotinonitrile

Intermediate VIIa was prepared from 6-chloro-2-methylnicotino nitrile(Manchester organics) and propionic acid using procedure analogous tointermediate Va. Yield: 14% MS (ES⁺), (M+H)⁺=193.10 for C₁₀H₉ClN₂.

Intermediate Vllb4-cyclopropyl-6-((diphenylmethylene)amino)-2-methylnicotinonitrile

Intermediate VIIb was prepared from Intermediate VIIa using procedureanalogous to intermediate Vb. Yield: 81% MS (ES⁺), (M+H)⁺=338.40 forC₂₃H₁₉N₃.

Intermediate VII 6-amino-4-cyclopropyl-2-methylnicotinonitrilehydrochloride

Intermediate VII was prepared from Intermediate VIIb using procedureanalogous to intermediate V. Yield: 38.6% MS (ES⁺), (M+H)⁺=174.14 forC₁₀H₁₁N₃.

Intermediate VIIIa 6-chloro-4-cyclobutyl-3-fluoro-2-methylpyridine

Intermediate VIIIa was prepared from 6-chloro-3-fluoro-2-methylpyridine(Matrix Scientific) and cyclobutanecarboxylic acid using procedureanalogous to intermediate Va. Yield: 21% MS (ES⁺), (M+H)⁺=200 forC₁₀H₁₁ClFN.

Intermediate VIIIb4-cyclobutyl-N-(diphenylmethylene)-5-fluoro-6-methylpyridin-2-amine

Intermediate VIIIb was prepared from Intermediate VIIIa using procedureanalogous to intermediate Vb. Yield: 40% MS (ES⁺), (M+H)⁺=346 forC₂₃H₂₁FN₂.

Intermediate VIII 4-cyclobutyl-5-fluoro-6-methylpyridin-2-aminehydrochloride

Intermediate VIII was prepared from Intermediate VIIIb using procedureanalogous to intermediate V. Yield: 88% ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.73-1.92 (m, 1H) 1.98-2.17 (m, 3 H) 2.21-2.33 (m, 2 H) 2.33-2.38 (m, 3H) 3.58-3.75 (m, 1 H) 6.72 (d, J=5.65 Hz, 1 H) 7.74 (br. s., 1 H) MS(ES⁺), (M+H)⁺=167.12 for C₁₀H₁₃FN₂.

Intermediate IXc 3,6-dichloro-2-methylpyridine

To a suspension of 5-chloro-6-methylpyridin-2-amine (7.5 g, 52.60 mmol,Combi-Blocks) in DCM (200 mL) was added copper(II) chloride (9.19 g,68.38 mmol) and stirred at for 10 min. tert-butyl nitrite (12.50 mL,105.20 mmol) was added and the stirring was continued further 30 min atRT. The colour was changed to dark blue. The reaction was monitored byLCMS. LCMS showed the completion of reaction. The reaction mixture waswashed with water, brine solution, and organic layer was dried on sodiumsulphate and concentrated under vacuum to get crude. The product waspurified by column chromatography using 5% ethyl acetate:hexane mixtureto get 3,6-dichloro-2-methylpyridine (3.80 g, 44.6 %) as a yellowliquid. MS (ES⁺), (M+H)⁺=162.15 for C₆H₅Cl₂N.

Intermediate IXa 3,6-dichloro-4-cyclopropyl-2-methylpyridine

Intermediate IXa was prepared from Intermediate IXc using procedureanalogous to intermediate Va. Yield: 23% MS (ES⁺), (M+H)⁺=202.24 forC₉H₉Cl₂N

Intermediate IXb5-chloro-4-cyclopropyl-N-(diphenylmethylene)-6-methylpyridin-2-amine

In a 100 ml RBF 3,6-dichloro-4-cyclopropyl-2-methylpyridine (250 mg,1.24 mmol), Benzenemethanimine, alpha-phenyl-(0.228 mL, 1.36 mmol) and9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (57.3 mg, 0.10 mmol) wastaken in toluene (6 mL) and the reaction mixture degassed for 5 min.Then Tris(dibenzylidene acetone) dipalladium(0) (45.3 mg, 0.05 mmol) andSodium tert-butoxide (357 mg, 3.71 mmol) were added. The RM was thenheated at 110° C. for 3 h under nitrogen. The reaction was monitored byLCMS and identified required mass. RM was filtered off on a celite bed.Acetic acid (40 μL, 2 eq) was added to filtrate. The filterate was thenadsorbed on silica and chromatographed with ethyl acetate /hexane to get5-chloro-4-cyclopropyl-N-(diphenylmethylene)-6-methylpyridin-2-amine(300 mg, 69.9 %) as a solid. MS (ES⁺), (M+H)⁺=347.59 for C₂₂H₉ClN₂.

Intermediate IX 5-chloro-4-cyclopropyl-6-methylpyridin-2-aminehydrochloride

Intermediate IX was prepared from Intermediate IXb using procedureanalogous to intermediate V. Yield: 48% MS (ES⁺), (M+H)⁺=183.45 forC₉H₁₁ClN₂.

Intermediate Xa (R)-tert-butyl4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

(R)-tert-butyl4-(2-chloro-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate(185 mg, 0.44 mmol, Intermediate IVa) was taken in a 50 ml thermalreactor and was dissolved in toluene (10 mL).4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride (89 mg,0.44 mmol, Intermediate V),9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (25.4 mg, 0.04 mmol),Tris(di benzylideneacetone) dipalladium(0) (20.08 mg, 0.02 mmol) andSodium tert-butoxide (84 mg, 0.88 mmol) were added into this and theresulting mixtures was refluxed at 120° C. under nitrogen for overnight.Reaction was monitored with LCMS and identified required mass. Reactionmixture was cooled and diluted with methanol and filtered through Celitebed and resultant filtrate was concentrated and purified over combiflashfollowed by Gilson preparative HPLC to get pure white solid of(R)-tert-butyl4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate(60.0 mg, 24.81 %) MS (ES⁺), (M+H)⁺=552.37 for C₂₈H₃₈FN₉O₂.

Intermediate Xb (R)-tert-butyl4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((1-ethyl-5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

This was prepared as described above for Intermediate Xa fromIntermediate IVb & Intermediate V. Yield: 23.12% MS (ES⁺), (M+H)⁺=567.60for C₂₉H₄₀FN₉O₂.

Intermediate Xc (R)-tert-butyl4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

This was prepared as described above for Intermediate Xa fromIntermediate IVd & Intermediate V. Yield: 45.5% MS (ES⁺), (M+H)⁺=539.44for C₂₆H₃₅FN₁₀O₂.

Intermediate Xd (R)-tert-butyl4-(2-((5-chloro-4-cyclopropyl-6-methylpyridin-2-yl)amino)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

This was prepared as described above for Intermediate Xa fromIntermediate IVa& Intermediate IX. Yield: 44.6% MS (ES⁺),(M+H)⁺=569.39for C₂₈H₃₈ClN₉O₂.

Intermediate Xe (R)-tert-butyl4-(2-((5-cyano-4-cyclopropyl-6-methylpyridin-2-yl)amino)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

This was prepared as described above for Intermediate Xa fromIntermediate IVa & Intermediate VII. Yield: 35.5% MS (ES⁺),(M+H)⁺=559.35 for C₂₉H₃₈N₁₀O₂.

Intermediate Xf (R)-tert-butyl4-(4-((1.5-dimethyl-1H-pyrazol-3-yl)amino)-2-((4-ethyl-5-fluoro-6-methylpyridin-2-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

This was prepared as described above for Intermediate Xa fromIntermediate IVa & Intermediate VI. Yield: 57.9% MS (ES⁺), (M+H)⁺=540.21for C₂₇H₃₈FN₉O₂.

Intermediate Xg (S)-tert-butyl4-(4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-2-((4-ethyl-5-fluoro-6-methylpyridin-2-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

This was prepared as described above for Intermediate Xa fromIntermediate IVe & Intermediate VI. Yield: 57.9% MS (ES⁺), (M+H)⁺=540.21for C₂₇H₃₈FN₉O₂.

Intermediate Xh (R)-tert-butyl4-(2-((4-cyclobutyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate(72.0 mg, 25.6%).

This was prepared as described above for Intermediate Xa fromIntermediate IVa & Intermediate VIII. Yield: 25.6% MS (ES⁺),(M+H)⁺=566.33 for C₂₉H₄₀FN₉O₂.

Intermediate Xi (R)-tert-butyl4-(2-((5-chloro-4-cyclopropyl-6-methylpyridin-2-yl)amino)-4-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

This was prepared as described above for Intermediate Xa fromIntermediate IVc & Intermediate IX. Yield: 46.0% MS (ES⁺), (M+H)⁺=555.26for C₂₆H₃₅ClN₁₀C₂.

Intermediate Xi (R)-tert-butyl4-(2-((5-chloro-4-cyclopropyl-6-methylpyridin-2-yl)amino)-4-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

This was prepared as described above for Intermediate Xa fromIntermediate IVd & Intermediate IX. Yield: 14.75% MS (ES⁺),(M+H)⁺=555.26 for C₂₆H₃₅ClN₁₀O₂.

Intermediate Xk (R)-tert-butyl4-(2-((3-cyclopropyl-4-fluoro-5-methylphenyl)amino)-4-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate

This was prepared as described above for Intermediate Xa fromIntermediate IVc & Intermediate V. Yield: 58.3% MS (ES⁺), (M+H)⁺=539.29for C₂₆H₃₅FN₁₀O₂.

Example 1N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1-methyl-1H-1,2,3-triazol-4-yl)-5-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine

This was prepared as described above for Intermediate Xa fromIntermediate IVf & Intermediate V. Yield: 21.28%, ¹H NMR (300 MHz,DMSO-d₆) δ ppm 0.70-0.82 (m, 2H) 1.04-1.15 (m, 2 H) 1.99-2.14 (m, 1H)2.26 (s, 3H) 2.36 (d, J=3.01 Hz, 3 H) 2.87 (t, J=4.43 Hz, 4 H) 4.05 (s,3 H) 6.55 (s, 1 H) 7.85 (d, J=5.09 Hz, 1 H) 8.07 (s, 1H) 8.51 (s, 1 H)8.94 (s, 1 H) 9.62 (s, 1 H). MS (ES⁺), (M+H)⁺=439 for C₂₁H₂₇FN₁₀.

Example 2(R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diaminedihydrochloride

In a 50 mL round-bottomed flask (R)-tert-butyl4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-5-yl)-2-methylpiperazine-1-carboxylate(55 mg, 0.10 mmol, Intermediate Xa) was taken in 1,4-dioxane (10 mL)colorless solution. 4N HCl in Dioxane (4 ml, 16.00 mmol) was addedslowly at rt. Reaction mass was stirred at RT for 2h shows reactioncompleted which is confirmed by LCMS. Reaction mass was concentrated andtriturated with acetonitrile to get white solid of(R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diamine(40.0 mg, 76%) ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.73-0.82 (m, 2 H)1.15-1.22 (m, 2 H) 1.29 (d, J=6.22 Hz, 3 H) 2.13 (t, J=4.71 Hz, 1 H)2.31 (s, 3 H) 2.54 (d, J=3.20 Hz, 3 H) 2.76-2.89 (m, 1 H) 2.95-3.18 (m,3 H) 3.25-3.38 (m, 1 H) 3.42 (br. s., 1 H) 3.56-3.80 (m, 4 H) 6.64-6.89(m, 2 H) 8.12 (s, 1 H) 9.38 (br. s., 1 H) 9.81 (br. s., 1 H) 10.29 (s, 1H) 11.39 (br. s., 1 H) 13.93 (br. s., 1 H) MS (ES⁺), (M+H)⁺=452.27 forC₂₃H₃₀FN₉.

Example 3(R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(l-ethyl-5-methyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diaminedihydrochloride

This was prepared as described above for Example 2 from Intermediate XbYield: 96%, ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.67-0.84 (m, 2 H) 1.12-1.21(m, 2 H) 1.22-1.36 (m, 6 H) 2.09-2.18 (m, 1 H) 2.32 (s, 3 H) 2.53 (d,J=3.20 Hz, 3 H) 2.76-2.86 (m, 1 H) 3.00 (d, J=5.09 Hz, 1 H) 3.05-3.19(m, 2 H) 3.24-3.52 (m, 2 H) 3.66 (br. s., 1 H) 4.05 (q, J=7.03 Hz, 2 H)6.68 (br. s., 1 H) 6.76 (br. s., 1 H) 8.09 (s, 1 H) 9.16 (br. s., 1 H)9.58 (br. s., 1 H) 10.31 (br. s., 1 H) 11.31 (br. s., 1 H) 13.90 (br.s., 1 H). MS (ES⁺), (M+H)⁺=466.29 for C₂₄H₃₂FN₉.

Example 4(R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1-methyl-1H-1,2,3-triazol-4-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diaminedihydrochloride

This was prepared as described above for Example 2 from Intermediate XcYield : 92%, ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.61-14.09 (m, 1H), 12.20(br. s., 1H), 10.97 (s, 1H), 9.65 (br. s., 1H), 8.91-9.29 (m, 2H), 8.13(s, 1H), 6.97 (d, J=4.90 Hz, 1H), 3.67 (br. s., 1H), 3.27-3.56 (m, 3H),2.98-3.27 (m, 3H), 2.68-2.94 (m, 1H), 2.03-2.28 (m, 2H), 1.07-1.38 (m,6H), 0.69-0.84 (m, 2H). MS (ES⁺), (M+H)⁺=439.37 for C₂₁H₂₇FN₁₀.

Example 5(R)-N2-(5-chloro-4-cyclopropyl-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diaminedihydrochloride

This was prepared as described above for Example 2 from Intermediate XdYield : 92%, ¹H NMR (300 MHz, DMSO-d₆) δ 9.39 (s, 1H), 8.05 (s, 1H),7.92-8.01 (m, 1H), 7.77 (s, 1H), 6.87 (s, 1H), 3.63 (s, 3H), 3.36-3.42(m, 1H), 2.63-3.00 (m, 7H), 2.04-2.40 (m, 7H), 0.91-1.18 (m, 8H),0.56-0.78 (m, 2H). MS (ES⁺), (M+H)⁺=468.40 for C₂₃H₃₀ClN₉.

Example 6(R)-4-cyclopropyl-6-((4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-5-(3-methylpiperazin-1-yl)pyrimidin-2-yl)amino)-2-methylnicotinonitriledihydrochloride

This was prepared as described above for Example 2 from Intermediate XeYield: 91%, ¹H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.54 Hz, 3 H)1.28 (d, J=6.22 Hz, 3 H) 2.31 (s, 3 H) 2.54 (d, J=3.01 Hz, 3 H) 2.68 (d,J=7.54 Hz, 2 H) 2.77-2.87 (m, 1 H) 3.12 (br. s., 2 H) 3.27-3.39 (m, 1 H)3.44 (br. s., 1 H) 3.64 (br. s., 1 H) 3.73 (s, 3 H) 6.72 (s, 1 H) 7.17(d, J=4.52 Hz, 1 H) 8.12 (s, 1 H) 9.28 (br. s., 1 H) 9.71 (br. s., 1H)10.27 (s, 1 H) 11.48 (s, 1 H) MS (ES⁺), (M+H)⁺=459.26 for C₂₄H₃₀N₁₀.

Example 7(R)-N4-C1,5-dimethyl-1H-pyrazol-3-yl)-N2-(4-ethyl-5-fluoro-6-methylpyridin-2-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diaminedihydrochloride

This was prepared as described above for Example 2 from Intermediate XfYield: 75%, ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.15-1.24 (m, 3 H) 1.29 (d,J=6.03 Hz, 3 H) 2.31 (s, 3 H) 2.54 (d, J=3.01 Hz, 3 H) 2.67 (q, J=1.66Hz, 2 H) 2.85 (d, J=1.49 Hz, 1 H) 2.96-3.22 (m, 3 H) 3.24-3.54 (m, 4 H)3.60-3.76 (m, 4 H) 6.74 (s, 1 H) 7.18 (d, J=4.33 Hz, 1 H) 8.13 (s, 1 H)9.40 (br. s., 1 H) 9.82 (br. s., 1 H) 10.28 (s, 1 H) 11.52 (br. s., 1 H)MS (ES⁺), (M+H)⁺=440.28 for C₂₂H₃₀FN₉.

Example 8(R)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-N2-(4-ethyl-5-fluoro-6-methylpyridin-2-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diaminedihydrochloride

This was prepared as described above for Example 2 from Intermediate XgYield: 75%, ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.15-1.24 (m, 3 H) 1.29 (d,J=6.03 Hz, 3 H) 2.31 (s, 3 H) 2.54 (d, J=3.01 Hz, 3 H) 2.67 (q, J=1.66Hz, 2 H) 2.85 (d, J=11.49 Hz, 1 H) 2.96-3.22 (m, 3 H) 3.24-3.54 (m, 4 H)3.60-3.76 (m, 4 H) 6.74 (s, 1 H) 7.18 (d, J=4.33 Hz, 1 H) 8.13 (s, 1 H)9.40 (br. s., 1 H) 9.82 (br. s., 1 H) 10.28 (s, 1 H) 11.52 (br. s., 1 H)MS (ES⁺), (M+H)⁺=440.28 for C₂₂H₃₀FN₉.

Example 9(R)-N2-(4-cyclobutyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diaminedihydrochloride

This was prepared as described above for Example 2 from Intermediate XhYield: 99%, ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.29 (d, J=6.40 Hz, 3 H)1.77-1.95 (m, 1 H) 2.08-2.19 (m, 3 H) 2.24-2.44 (m, 5 H) 2.51-2.55 (m, 3H) 2.78-2.93 (m, 1 H) 2.98-3.19 (m, 3 H) 3.31 (br. s., 1 H) 3.40 (d,J=10.74 Hz, 1 H) 3.57-3.80 (m, 5 H) 6.78 (s, 1H) 7.22 (d, J=4.71 Hz, 1H) 8.14 (s, 1 H) 9.47 (d, J=9.23 Hz, 1 H) 9.92 (d, J=8.85 Hz, 1 H) 10.31(s, 1 H) 11.57 (s, 1 H) 13.96 (br. s., 1 H). MS (ES⁺), (M+H)⁺=466 forC₂₄H₃₂FN₉.

Example 10(R)-N2-(5-chloro-4-cyclopropyl-6-methylpyridin-2-yl)-N4-(2-methyl-2H-1,2,3-triazol-4-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diaminedihydochloride

This was prepared as described above for Example 2 from Intermediate XiYield: 99%, ¹H NMR (300 MHz, DMSO-d₆) δ 0.63-0.88 (m, 2H) 1.14-1.37 (m,6H), 2.19-2.34 (m, 1H), 2.68 (s, 4H), 2.83 (t, J=11.30 Hz, 1H),2.95-3.25 (m, 4H), 3.29-3.59 (m, 3H), 4.17 (s, 4H), 6.82 (s, 1H), 8.21(s, 1H), 8.46-8.63 (m, 1H), 9.33 (br. s., 1H), 9.81 (br. s., 1H), 10.90(br. s., 1H), 11.73 (br. s., 1H), MS (ES⁺), (M+H)⁺=455 for C₂₁H₂₇ClN₁₀.

Example 11(R)-N2-(5-chloro-4-cyclopropyl-6-methylpyridin-2-yl)-N4-(1-methyl-1H-1,2,3-triazol-4-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diaminedihydrochloride

This was prepared as described above for Example 2 from Intermediate XjYield: 79%, ¹H NMR (300 MHz, DMSO-d₆) δ 12.25 (br. s., 1H), 10.98 (br.s., 1H), 9.62 (br. s., 1H), 9.14 (br. s., 2H), 8.16 (s, 1H), 7.02 (br.s., 1H), 4.13 (s, 4H), 3.38 (s, 5H), 2.97-3.29 (m, 4H), 2.61-2.93 (m,6H), 2.27 (br. s., 2H), 1.06-1.40 (m, 7H), 0.77 (br. s., 3H) MS (ES⁺),(M+H)⁺=455 for C₂₁H₂₇ClN₁₀.

Example 12(R)-N2-(5-Fluoro-4-cyclopropyl-6-methylpyridin-2-yl)-N4-(2-methyl-2H-1,2,3-triazol-4-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diaminedihydochloride

This was prepared as described above for Example 2 from Intermediate XkYield: 92% MS (ES⁺), (M+H)⁺=438.36 for C₂₂H₂₈FN₉.

Example 13(R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine

In a 50 mL round-bottomed flask(R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diaminehydrochloride (190 mg, 0.42 mmol, Example 2) was taken in DCM (2 mL) togive a yellow suspension. To this Hunig's Base (0.184 mL, 1.05 mmol) wasadded and the suspension turned clear. After 10 minutes, it turned intoa white suspension. After another 10 minutes, the mixture wasconcentrated to dryness. Resultant residue was dissolved in ethanol(absolute, 99.5%) (3 mL) and formaldehyde (0.042 mL, 0.63 mmol) wasadded and stirred for 10 minutes. White suspension slowly cleared toyellow solution. To this clear solution sodium cyanoborohydride (26.4mg, 0.42 mmol) was added in one portion to get white suspension. After30 minutes LCMS showed completion of reaction. The reaction mixture wasconcentrated and the crude was purified through reverse phase HPLCGILSON instrument to get the pure solid of(R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine (80mg, 40.8%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.67-0.78 (m, 2 H) 1.00 (d,J=6.22 Hz, 3 H) 1.02-1.08 (m, 2 H) 1.96-2.10 (m, 1 H) 2.23 (s, 7 H)2.30-2.38 (m, 4 H) 2.73-2.96 (m, 4 H) 3.33 (s, 3 H) 6.83 (s, 1 H) 7.67(d, J=5.09 Hz, 1 H) 8.00 (s, 1 H) 8.03 (s, 1 H) 9.26 (s, 1 H) MS (ES⁺),(M+H)⁺=466.45 for C₂₁H₃₂FN₉.

Example 14(R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-5-(3,4-dimethylpiperazin-1-yl)-N4-(1-methyl-1H-1,2,3-triazol-4-yl)pyrimidine-2,4-diamine

This was prepared as described above for Example 13 from Example 4Yield: 12%, ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.71-0.81 (m, 2 H) 0.81-0.90(m, 1 H) 1.01 (d, J=6.03 Hz, 3 H) 1.05-1.16 (m, 2 H) 1.20-1.32 (m, 2 H)1.99-2.13 (m, 1 H) 2.24 (s, 3 H) 2.36 (d, J=3.01 Hz, 4 H) 2.69-2.98 (m,5 H) 2.69-2.98 (m, 5 H) 4.05 (s, 3 H) 7.76-7.94 (m, 1 H) 8.05 (s, 1 H)8.40-8.60 (m, 1 H) 8.92 (s, 1 H) 9.47-9.71 (m, 1 H). MS (ES⁺),(M+H)⁺=453.25 for C₂₂H₂₉FN₁₀.

Example 15(R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-5-(3,4-dimethylpiperazin-1-yl)-N4-(2-methyl-2H-1,2,3-triazol-4-yl)pyrimidine-2,4-diamine

This was prepared as described above for Example 13 from Example 11Yield: 28%, ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.28 (s, 3 H) 3.78-4.09 (m,5 H) 5.76 (s, 2 H) 5.97-6.51 (m, 1 H) 7.36 (t, J=7.82 Hz, 1 H) 7.71 (d,J=7.91 Hz, 1 H) 7.91 (d, J=7.54 Hz, 1 H) 8.41 (s, 1 H) 8.57 (s, 1 H)10.05 (t, J=6.12 Hz, 1 H). MS (ES⁺), (M+H)⁺=453.34 for C₂₂H₂₉FN₁₀.

Example 16 Biological Activities

The compounds of Formula (I) are of interest due to their potentantimalarial effects. The ability of the invention compounds disclosedherein to achieve an antimalarial effect may be evaluated with regard totheir ability to inhibit the growth of Plasmodium species like P.falciparum using an assay based on the following protocol.

Further, compounds of the invention (Examples 2 and 13) were also testedagainst field isolates of falciparum and vivax malaria, along with threecontrol antimalarials as described in the protocol below. The activitydata is shown in Table 1.

TABLE 1 Plasmodium field isolates P. falciparum P. vivax Compounds IC₅₀nM IC₅₀ nM Chloroquine 60.8 40.2 Piperaquine 16.9 5.9 Artesunate 15.14.79 Example 13 74.6 85.6 Example 2 63.6 81.0

Those data supports the fact that compounds of the invention havecomparable activities towards falciparum and vivax malaria.

Measuring In Vitro Antiplasmodial Activity

The test samples were tested in duplicate on two separate occasionsagainst chloroquine sensitive NF54 (MRA-1000, MR⁴, ATCC, Manassas, Va.)and chloroquine-resistant K1 strain of P. falciparum. A modified methodof Trager and Jensen was employed to maintain continuous in vitrocultures of asexual blood stages of P. Falciparum (Trageret al., 1976,Science, 193, 673-675). Quantitative assessment of antiplasmodialactivity in vitro was determined using the SYBR I method as describedearlier (Johnson et al., 2007, Antimicrob. Agents Chemother., 51,1926-1933).

The percent inhibition with respect to the drug-free control was plottedagainst the logarithm of drug concentration. The growth inhibitioncurves were fitted by non-linear regression using the sigmoidaldose-response (variable slope) formula to yield theconcentration-response curves. The EC₅₀ value of the compound wasdefined as the lowest concentration at which 50% inhibition wasobserved. Chloroquine diphosphate (CQ) (Sigma), artesunate (Sigma), andpyrimethamine were used as reference drugs in all experiments.

The compounds of Formula (I) according to invention evaluated in anantimalarial activity test to determine their inhibitory activityagainst Plasmodium falciparum (both NF54 and k1 strains) and results arereported in Table 2 below:

TABLE 2 Example Pf IC_(50—)NF54(nM) Pf IC_(50—)K1(nM) 1 15 24 2 14 19 317 14 4 33 51 5 23 48 6 31 45 7 27 45 8 35 44 9 25 48 10 13 19 11 30 5012 39 82 13 9 15 14 33 69 15 17 37 Chloroquinine 11 >150 Pyrimethamine64 7900

In Vivo Efficacy in the Mouse Malaria Model

In vivo efficacy against blood stages was measured in mice infected withPlasmodium berghei after four (once daily) days of dosing by oral route.Detailed protocol for this four day suppressive test is described inFidock et al 2004, Nature Reviews Drug Discovery (3), p 509. Percentinhibition of growth of parasites in mouse blood is shown in Table 3below.

TABLE 3 Compound Dose (mg/kg) % Inhibition Example 7 3 6 10 28 30 100Example 10 10 60 15 75 30 100 Example 13 3 0 10 42 30 100

Ex Vivo Activity of Examples 2 and 13 Against Drug Resistant P.falciparum and P. vivax Field Isolates

Standard anti-malarial drugs chloroquine (CQ), amodiaquine (AQ),piperaquine (PIP), mefloquine (MFQ), and artesunate (AS), and compoundsof the invention were prepared as 1 mg/mL stock solutions in H₂O ordimethyl sulfoxide (DMSO) according to the manufacturers instructions.Drug plates were pre-dosed by diluting the compounds in 50% Methanolfollowed by lyophilisation and stored at 4° C.

Plasmodium isolates were collected from patients attending malariaclinics in Timika (Papua, Indonesia), a region endemic formultidrug-resistant strains of P. vivax and P. falciparum. Patients withsymptomatic malaria presenting to an outpatient facility were recruitedinto the study if singly infected with P. falciparum or P. vivax, with aparasitaemia of between 2,000 μl−1 and 80,000 μl−1, and the majority(>80%) of parasites at ring stage of development. Venous blood (5 mL)was collected by venepuncture and after removal of host white bloodcells by using cellulose (Sigma-Aldrich, Australia) filtration, packedinfected red blood cells (iRBCs) were used for the ex vivo drugsusceptibility assay.

Drug susceptibility of P. vivax and P. falciparum isolates was measuredusing a protocol modified from the WHO microtest as described previously(Marfurt et al., 2011, Antimicrob Agents Chemother., 55(9):4461). Twohundred μL of a 2% haematocrit Blood Media Mixture (BMM), consisting ofRPMI 1640 medium plus 10% AB+ human serum (P. falciparum) or McCoy's 5Amedium plus 20% AB+ human serum (P. vivax) was added to each well ofpre-dosed drug plates containing 11 serial concentrations (2-folddilutions) of the anti-malarials (maximum concentration shown inbrackets) CQ (2,992 nM), AQ (158 nM), PIP (1,029 nM), MFQ (338 nM), AS(49 nM), Compound of the invention (2,146 nM). A candle jar was used tomature the parasites at 37.0° C. for 35-56 hours. Incubation was stoppedwhen >40% of ring stage parasites had reached mature schizont stage inthe drug-free control wells.

Thick blood films made from each well were stained with 5% Giemsasolution for 30 minutes and examined microscopically. The number ofschizonts per 200 asexual stage parasites was determined for each drugconcentration and normalised to the control well. The dose-response datawere analysed using nonlinear regression analysis (WinNonLn 4.1,Pharsight Corporation) and the IC₅₀ value derived using an inhibitorysigmoid Emax model. Ex vivo IC₅₀ data were only used from predictedcurves where the E_(max) and E₀ were within 15% of 100 and 1,respectively. Drug plate quality was assured by running schizontmaturation assays (two independent experiments) with thechloroquine-resistant strain K1 and the chloroquine-sensitive strainFC27.

For microscopy slide reading QC, two randomly selected drugs per isolatewere read by a second microscopist. If the raw data derived by the twomicroscopists lead to a dramatic shift in the IC₅₀ estimates of theselected drugs, the whole assay (i.e., all standard drugs andexperimental compounds) was re-read by a second reader and the resultscompared. If necessary, discrepant results were resolved by a thirdreading by an expert microscopist.

Metabolic Stability Assay (Rat/Human Hepatocyte Clint)

Viability of cryopreserved hepatocytes was determined using trypan blueand the cell concentration was adjusted to 10⁶ cells per mL withLeibovitz L-15 Buffer. μM compound (in Acetonitrile; 0.01% DMSO) wasincubated with 500 μL of hepatocytes (1 million cells per mL) in a NUNCplate. Reaction was stopped at different time points (0, 5, 15, 30, 60,90 and 120 min) by addition of 3 volumes of chilled acetonitrile to 100μL of reaction mixture and centrifuged at 4° C. for 15 min. Supernatantswere analyzed using LC-MS/MS for substrate depletion.

Determination of Blood: Plasma (BP) Ratio

The incubation plate and the dog blood/plasma was preheated at 37° C.for 10 minutes. 2 μL of working solution of each compound was added to398 μL of dog reference plasma or blood to achieve a final concentrationof 10 μM. Plates were incubated at 37° C. with shaking for 30 min. Afterincubation, the blood samples are spun for 10 min. at 4,000 rpm (37° C.)and the plasma samples were stored at 37° C. Aliquots (100 μL) of plasmaseparated from centrifuged whole blood samples and reference plasmasamples were transferred into the 96 well plates. 400 μL of coldacetonitrile was added to precipitate protein and release compound.After vortexing for 10 min., plates were centrifuged for 30 min. at4,000 rpm. 250 μL of the supernatant was transferred to new 96-wellplates and centrifuged again at 4,000 rpm for 30 min. 100 μL of thesupernatant was used for analysis by LC-MS/MS.

Plasma Protein Binding Assay

Protein binding is measured using the equilibrium dialysis technique.Compound is added to 10% plasma giving a concentration of 20 μM anddialysed with isotonic buffer for 18 hours at 37° C. The plasma andbuffer solutions are analysed using generic LCUVMS and the firstapparent binding constant for the compound derived. The binding constantis then used to determine the % free in 100% plasma.

Prediction of Human Pharmacokinetic (PK) Parameters

Well stirred model was used for predicting human CL using humanhepatocyte Clint and free fraction (fu) in human plasma. Liver bloodflow rates, liver weights, hepatocellularity and in vitro in vivocorrelation/extrapolation (IVIVC/E) templates routinely employed (Smithet al., Pharmacokinetics and Metabolism in Drug Design, Methods andPrinciples in Medicinal Chemistry Volume 13, 2004, Wiley-VCH, Weinheim,Germany) were used for prediction.

Pharmacokinetic Studies

All in vivo studies were approved by the institutional animal ethicscommittee. Pharmacokinetics following IV bolus (IVPK) or oraladministration (POPK) of compounds was determined in male Wistar rats ormale Beagle dogs. For IVPK in rats, example 7 and example 10 wereadministered as solutions in 20% DMA, 80% phosphate buffered saline andexample 13 was administered as a solution in 10% v/v NMP, 20% v/v DMA insaline. For POPK, example 7, example 10 were administered as suspensionsin 20% DMA, 80% phosphate buffered saline and example 13 wasadministered as a suspension in 0.5% HPMC, and 0.1% Tween 80 through anoral gavage. Example 13 was administered in dogs as a solution in 10%Ethanol, 30% PEG 400, 60% saline for IVPK and as a suspension in 0.5%HPMC, and 0.1% Tween 80 for POPK. Doses used for rat and dog PK were 0.5mg/kg for example 7 and 10 or 2 mg/kg for example 13 (IVPK). Dose of 5mg/kg for example 7 & 10 used during PO PK. Dose 10 mg/kg used forexample 13 during PO PK studies. Blood samples were collected at 8 to 13time points (0, 0.0833, 0.25, 0.283, 0.333, 0.417, 0.75, 1.25, 3.25,6.25, 12.25 24.25 h for dog IVPK; 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12,24, 32, 48 h for dog POPK; 0.083, 0.25, 0.5, 1, 2, 4, 7, 24 h for ratIVPK; 0.25, 1, 3, 6, 12, 24, 36, 48 h for rat POPK) after dosing. Blood(rats) or plasma (dog) samples were analysed by LC-MS/MS. PK parameterswere estimated by non-compartmental analysis in Phoenix®.

Pharmacokinetics in the blood of infected Pf/SCID mice: Peripheral bloodsamples (25 μl) were taken at different times (0.25, 0.5, 1, 2, 4, 6, 8and 23 hours), mixed with 25 μl of H₂O mili Q and immediately frozen ondry ice. The frozen samples were stored at −80° C. until analysis.Vehicle-treated mice experienced the same blood-sampling regimen. Bloodsamples were processed by liquid-liquid extraction by mixing 10 μldiluted blood with 180 μl AcN:MeOH (80:20; v:v) mixture. Quantitativeanalysis by LC/MSMS was performed using UPLC (Waters) and Sciex API4000.The lower limit of quantification (LLOQ) in this assay was 0.005 μg/ml.

CYP Inhibition Assay

This study was conducted using specific substrates for 5 major human CYPisozymes. These substrates were used as a cocktail (phenacetin,diclofenac, S-mephenytoin, bufuralol and midazolam which arepredominantly metabolised by CYP 1A2, 2C9, 2C19, 2D6 and 3A4/5,respectively) at concentrations equivalent to their respective Kmvalues. LC-MS-MS (MRM mode) was used to follow the formation of the CYPspecific metabolites. A decrease in the formation of the metabolites inpeak area to vehicle control was used to calculate the IC₅₀ value. Inaddition, as a positive control, a cocktail of five standard inhibitors,specific for an individual CYP (α-naphthoflavone,sulphaphenazole,N-3-benzylnirvanol, quinidine and ketoconazole, which specificallyinhibit CYP 1A2, 2C9, 2C19, 2D6 and 3A4/5, respectively) was incubated.Test compound was used at 6 different concentrations (30, 10, 3, 1, 0.3,0.1 μM) to estimate IC₅₀.

The incubation was carried out in 96 deep well plates. Mixture of 180 μLof 20 mg/mL HLM and 90 μL of substrates cocktail solution was added to15840 μL of phosphate buffer and 179 μL of this mixture was mixed with 1μL of the test compound, inhibitor cocktail solution or vehicle in eachwell. The final concentration of DMSO: ACN in the assaymix was 0.3:0.7%v/v. The incubation plate was placed into the water bath and pre-warmedat 37° C. for 5 min before the reactions were started by the addition of20 μL of 10 mmol/L NADPH solution in phosphate buffer. After theaddition of NADPH, the incubation plate was incubated at 37° C. for afurther 5 min. The reaction was quenched by the addition of 1 volume(200 μL) of cold ACN containing 3% formic acid and 40 nmol/L verapamil.The plates were kept on ice for 20 min and then centrifuged at 4000 rpmfor 30 min to precipitate protein. The supernatant 180 μL wastransferred to the analysis plate for LC/MS/MS analysis.

Caco2 Permeability Assay

Permeability in a Caco2 monolayer was determined at 10 μM. The Caco-2cell monolayers were washed once with HBSS. TEER was measured bothbefore and after performing all the transport experiments. Papp wasmeasured in apical A to basolateral B direction. Transport buffer, 800μL, (HBSS, pH 7.4) was first dispensed to the basal side of themonolayer. The assay was then initiated by adding 200 μL of compoundsolution to the apical side (all test compounds were diluted in HBSS, pH6.5, with 1% DMSO as co-solvent). Two μL and 200 μL of samples werewithdrawn, before and at 45 and 120 min post addition of test compound,from the apical donor compartment and the basolateral receivercompartment, respectively. The transwell plates were incubated at 37° C.on a shaker at 480 rpm inside the incubator. All samples wereimmediately analysed by LC-MS/MS. A passive permeability was determinedby complete chemical inhibition of the three major efflux transportersABCB1 (P-gp), ABCG2 (BCRP) and ABCC2 (MRP2) in Caco-2 cells using acocktail of chemical inhibitors; quinidine (P-gp), sulfasalazine (BCRP)and benzbromarone (MRP2)).

The apparent permeability coefficient (P_(app)) was calculated accordingto the following equation:

P _(app)=(ΔQ/Δt)/(A×C _(D)) [cm/s]  (1)

where (ΔQ/Δt) [cm/s] is the cumulative amount of test compoundtransported over time to the basolateral (receiver) side, A is thesurface area of the monolayer membrane (cm²) and C_(D) is the averagedrug concentration in the donor chamber over the period which (ΔQ/Δt)was determined. Hep Clint, PPB, BP ratio and predicted/observedpharmacokinetic properties are presented in Table 4 below:

TABLE 4 Hep. Predicted CL Vss Oral ½ life Clint BP CLh blood blood blood‘F’ (PO PK) Compound Species (μl/min/1E6) ratio Fup (ml/min/kg)(ml/min/kg) (L/kg) (%) (h) Ex. 10 Rat 8.3 1.7 0.04 16.10 22.5 9.7 17 30Ex. 13 11.3  1.06 0.04 18.80  9.8 7.9 80 10 Ex. 7 5.6 2.2 0.06 24.2026.6 12 31 10 Ex. 10 Dog 5.1 1.7 0.04 12.70 ND ND ND ND Ex. 13 9.3 1.350.04 20.80 19.0 16.0 82  9 Ex. 7 ND ND ND ND ND ND ND ND Ex. 10 Human1.8 1.8 0.04 3.10 ND ND ND ND Ex. 13 3.1 1.1 0.03 4.80 ND ND ND ND Ex. 72.7 1.3 0.03 3.30 ND ND ND ND ND—not determined.

Since, faster reduction in the blood parasite burden is essential toprovide quick relief from clinical symptoms and to minimise the risk ofemergence of drug resistance, the compounds of the invention werefurther evaluated for their in vitro PK/Pharmacodynamic properties:

When tested in an in vitro parasite reduction ratio (PRR) assay (LeManach, et al., 2013, Malar J., 16, 424-430), Example 13 produceda >4-log kill after 48 hours of exposure, an effect similar tochloroquine in the same assay.

In the Pf/SCID model¹ as described above, Example 13 cleared Pfparasites to below detection limit following 4 days of daily treatmentwith 20 mg/kg dose administered through the oral route. A maximum killrate was observed at 40 mg/kg. Blood C_(min) (0.04 μM) observed at thisdose was considered the minimum parasiticidal concentration (MPC) forthe human dose prediction.

CYP Inhibition

Example 7, 10 and 13 did not inhibit human CYP 3A4, 2D6, 2C9, 2C19, or1A2. The IC₅₀s were >30 μM. The IC₅₀s in the time dependent inhibitionassays were >56 μM.

Caco2 Permeability (pH 6.5/7.4)

Data are presented in Table 5 below:

TABLE 5 Papp A to B Papp A to B (passive) Compound (1E−6 cm/s) (1E−6cm/s) Example 10 3.8 15.6 Example 13 19.5 36.0 Example 7 5.0 19.9

Identification of In Vivo Metabolites

Metabolites of Example 13 were identified both in vitro and in vivousing the following models:

-   -   In vitro: Compound of Example 13 was incubated with human (HLM)        or rat (RLM) liver microsomes (1 mg/ml protein concentration in        100 mM phosphate buffer, pH 7.4) at a final concentration of 10        μM in the presence of 2 mM NADPH. The reactive intermediates        were trapped by including 2 mM glutathione (GSH) or N-acetyl        cysteine (NAC) in the reaction mix.    -   In vivo in bile duct cannulated rats: Example 13 was        administered intravenously (IV) as a bolus through the jugular        vein at a dose of 2 mg/kg or 4 mg/kg of body weight for control        (n=3) or BDC rats (n=2), respectively. Blood samples were        collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h through        the carotid artery, bile samples were collected at 0-2 h, 2-4 h,        4-6 h, 6-8 h and 8-24 h intervals and urine samples were        collected at 0-8 h and 8-24 h intervals. The bile and urine        samples were analyzed for the presence of parent and metabolites        and blood sample was analyzed for the presence of parent. Data        are presented under Table 6 below.

TABLE 6 Proposed Rt Metabolite Presence of Peak (min) (m/z) Rat HumanMouse Liver Ex. 2 22.7 N-demethylation ✓ ✓ ✓ microsomes or (452)Hepatocytes

Those studies supported the fact that compound of Example 2 is an activemetabolite of compound of Example 13 and is formed both in vitro and invivo. Percent conversion to the active metabolite was highest in mousefollowed by rat and then human liver microsomes.

Importantly, there was no unique metabolite identified in the presenceof HLM or Hu hepatocytes. There was no GSH or NAC adduct formation.Hence there were no reactive metabolites formed in vitro.

1-28. (canceled)
 29. A compound of Formula (I):

or a complex, hydrate, solvate, or polymorph, tautomer, geometricalisomer, optically active form or a pharmaceutically acceptable saltthereof, wherein: HAR is a 5 membered heteroaryl ring system selectedfrom:

R¹ in each occurrence is independently selected from H, C₁₋₆alkyl, CF₃and C₃-C₅ cycloalkyl; R² in each occurrence is independently selectedfrom halo, —CN and C₁₋₆ alkyl; R³ in each occurrence is selected from H,C₁₋₆ alkyl, C₃-C₅ cycloalkyl and CF₃; R⁴ in each occurrence isindependently selected from H and C₁₋₆ alkyl; R⁵ in each occurrence isindependently selected from H and C₁₋₆ alkyl; and R⁶ in each occurrenceis independently selected from H and C₁₋₆ alkyl.
 30. The compound ofclaim 29, wherein R¹ is C₁₋₆ alkyl.
 31. The compound of claim 29,wherein R² is halogen.
 32. The compound of claim 29, wherein R³ is C₃-C₅cycloalkyl.
 33. The compound of claim 29, wherein R³ is C₁₋₆ alkyl. 34.The compound of claim 29, R⁴ is C₁₋₆ alkyl.
 35. The compound of claim29, wherein R⁵ is hydrogen.
 36. The compound of claim 29, wherein R⁶ isH.
 37. The compound of claim 29, wherein R⁶ is C₁₋₆ alkyl.
 38. Thecompound of claim 29, wherein HAR is selected from the following group:


39. The compound of claim 29, wherein R¹ is methyl; R² is selected fromfluorine, chlorine and CN; R³ is selected from cyclobutyl, ethyl andcyclopropyl; R⁴ is selected from hydrogen and methyl; R⁵ is hydrogen; R⁶is selected from hydrogen and methyl; and HAR is selected from:


40. The compound of claim 29, wherein the compound is selected from thefollowing group:N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-(4-methylpiperazin-1-yl)-N4-(1-methyltriazol-4-yl)pyrimidine-2,4-diamine;N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-N4-(1,5-dimethylpyrazol-3-yl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-N4-(1-ethyl-5-methyl-pyrazol-3-yl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[(3R)-3-methylpiperazin-1-yl]-N4-(1-methyltriazol-4-yl)pyrimidine-2,4-diamine;N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-N4-(1,5-dimethylpyrazol-3-yl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;4-cyclopropyl-6-[[4-[(1,5-dimethylpyrazol-3-yl)amino]-5-[3-methylpiperazin-1-yl]pyrimidin-2-yl]amino]-2-methyl-pyridine-3-carbonitrile;N4-(1,5-dimethylpyrazol-3-yl)-N2-(4-ethyl-5-fluoro-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;N4-(1,5-dimethylpyrazol-3-yl)-N2-(4-ethyl-5-fluoro-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;N2-(4-cyclobutyl-5-fluoro-6-methyl-2-pyridyl)-N4-(1,5-dimethylpyrazol-3-yl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine;N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]-N4-(2-methyltriazol-4-yl)pyrimidine-2,4-diamine;N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]-N4-(1-methyltriazol-4-yl)pyrimidine-2,4-diamine;N2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]-N4-(2-methyltriazol-4-yl)pyrimidine-2,4-diamine;N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[3,4-dimethylpiperazin-1-yl]-N4-(1,5-dimethylpyrazol-3-yl)pyrimidine-2,4-diamine;N2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[3,4-dimethylpiperazin-1-yl]-N4-(l-methyltriazol-4-yl)pyrimidine-2,4-diamine; andN2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[3,4-dimethylpiperazin-1-yl]-N4-(2-methyltriazol-4-yl)pyrimidine-2,4-diamine; as wellas pharmaceutically acceptable salts, complexes, hydrates, solvates,tautomers, polymorphs, racemic mixtures, optically active forms andpharmaceutically active derivative thereof.
 41. The compound of claim29, wherein the compound is selected fromN2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-5-[3,4-dimethylpiperazin-1-yl]-N4-(1,5-dimethylpyrazol-3-yl)pyrimidine-2,4-diamineand its active metaboliteN2-(4-cyclopropyl-5-fluoro-6-methyl-2-pyridyl)-N4-(1,5-dimethylpyrazol-3-yl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine.42. The compound of claim 29, wherein the compound isN4-(1,5-dimethylpyrazol-3-yl)-N2-(4-ethyl-5-fluoro-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine.43. The compound of claim 29, whereinN2-(5-chloro-4-cyclopropyl-6-methyl-2-pyridyl)-5-[3-methylpiperazin-1-yl]-N4-(2-methyltriazol-4-yl)pyrimidine-2,4-diamine.
 44. The compound of claim 29,wherein the compound is an R enantiomer.
 45. A pharmaceuticalcomposition comprising a compound of claim 29, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable diluent,excipient or carrier.
 46. The pharmaceutical composition of claim 45further comprising at least one further antimalarial agent.
 47. Thepharmaceutical composition of claim 46 wherein the further antimalarialagent is selected from artemisinin or an artimisinin derivative,chloroquinine, mefloquine, quinine, atoquone/proguanil, doxycycline,hydroxychloroquinine, halofantrine, pyronaridine, lumefantrine,pyrmethamine-sulfadoxine, piperaquine, amodiaquine, atovaquone,proguanil hydrochloride,Spiro[3H-indole-3,1′-[1H]pyrido[3,4-b]indol]-2(1H)-one (CAS RegistryNumber: 1193314-23-6),5,7′-dichloro-6′-fluoro-2′,3′,4′,9′-tetrahydro-3′-methyl-,(1′R,3′S)-],Sulfur,[4-[[2-(1,1-difluoroethyl)-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]amino]phenyl]pentafluoro-](CAS Registry Number: 1282041-94-4), Morpholine,4-[2-(4-cis-dispiro[cyclohexane-[1,3′-[1,2,4]trioxolane-5′,2″-tricyclo[3.3.1.13,7]decan]-4-ylphenoxy)ethyl]-](CAS Registry Number: 1029939-86-3), quinacrine,primaquine, tafenaquine, doxycycline, ferroquine, and arterolane.
 48. Amethod of treating or preventing malaria or a parasitic infection causedby Plasmodium species, comprising administering to a warm-blooded animalin need thereof an effective amount of a compound of claim 29 or acomplex, hydrate, solvate, or polymorph, tautomer, geometrical isomer,optically active form or pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.
 49. The method of claim 48, whereinthe compound is administered in combination with a co-agent useful inthe treatment and prevention of malaria.
 50. A process for thepreparation of a compound of Formula (I) comprising the step of reactinga derivative according to Formula (X) to lead to a compound of Formula(I) under acidic conditions:

wherein R₁, R², R³, R⁴, R⁵ and HAR are as defined in claim 29 and R is aprotecting group.
 51. A process for the preparation of an compound ofFormula (I) comprising the step of reacting a derivative according toFormula (IV) with a derivative of Formula (V) to lead to an intermediateof Formula (X) under palladium catalysed amination conditions asfollows:

wherein R is R⁶ and R⁶ is alkyl.